Heteroaryl-substituted acetone derivatives as inhibitors of phospholipase A2

ABSTRACT

The invention relates to novel heteroaryl substituted acetone derivatives which inhibit the enzyme phospholipase A 2 , pharmaceutical preparations containing these compounds and a method of producing these compounds.

This application claims priority to German Patent Application No. 103 05089.2 filed Feb. 7, 2003, the contents of which are incorporated byreference herein in its entirety.

The present invention relates to novel heteroaryl substituted acetonederivatives inhibiting the phospholipase A₂ enzyme. These compounds aresuited as drugs for preventing and treating diseases caused orcontributorily caused by an increased activity of this enzyme, such asinflammations, pain, fever, allergies, asthma, psoriasis and endotoxicshock. The invention also relates to methods of synthesizing thesecompounds as well as pharmaceutical preparations containing thesecompounds.

The term “phospholipase A₂” comprises the major and diverse group ofenzymes which cleave phospholipids at the sn-2 position thereby formingfree fatty acids and lysophospholipids. If the released fatty acid isarachidonic acid, the latter can be metabolized into the prostaglandinsand thromboxanes via the cyclooxygenase route and into the leukotrienesand other hydroxylated fatty acids via the lipoxygenase route. Theprostaglandins are considerably involved in the formation of pain andfever and in inflammatory responses. Leukotrienes are importantmediators in the case of inflammatory processes and anaphylactic andallergic processes (Forth et al., Aligemeine und Spezielle Pharmakologieund Toxikologie, Spektrum Akademischer Verlag Heidelberg, Berlin,Oxford, 1998).

The lysophospholipids formed by phospholipase A₂ have cell-damagingproperties. Lysophosphatidylserine releases the histamine involved inallergic processes (Moreno et al., Agents Actions 1992, 36, 258). Inaddition, lysophosphatidylcholine is metabolized into theplatelet-activating factor (PAF) which is also an important mediator,e.g. in the case of inflammations.

Various phospholipase A₂ forms are known. They comprise Ca²⁺-dependentlow-molecular secretory phospholipases A₂ (sPLA₂), CA²⁺-independenthigh-molecular phospholipases A₂ (iPLA₂), CA²⁺-dependent high-molecularcytosolic phospholipases A₂ (cPLA₂) and Ca²⁺-independentlipoprotein-associated phospholipases A₂ (LP-PLA₂), formerly alsoreferred to as PAF acetylhydrolase (Six et al., Biochim. Biophys. Acta.,2000, 1488, 1-19). According to the current state of knowledge, thecytosolic phospholipase A₂ (cPLA₂) plays the key role in thebiosynthesis of prostaglandins, leukotrienes, PAFs andlysophospholipids. This was demonstrated inter alia by studies withcPLA₂ knock-out mice, i.e. mice no longer having this enzyme (Uozumi etal., Nature 1997, 390, 618-622; Bonventre et al., Nature 1997, 390,622-625, Dennis et al., Journal of Experimental Medicine 2002, 196,349-357).

Thus, excess stimulation of this enzyme can result in a number ofchronic and acute diseases, such as asthma, cerebral ischemia (Clemenset al., Stroke 1996, 27, 527-535), Alzheimer's disease (Stephenson etal., Neurobiology of Stroke, 1996, 3, 51-63), rheumatoid arthritis(Huang et al., Mediators of Inflammation, 1994, 3, 307-308), chronicskin diseases and damage to the skin caused by U.V. rays (Gresham etal., American Journal of Physiology 1996, 270, C1037-C1050).

Inhibitors of cPLA₂ can thus be useful for a number of inflammatorydiseases.

Inhibitors of cytosolic Phospholipase A₂ have already been described inthe literature (Lehr, Drugs of the Future, 2000, 25, 823-832).

For example, 1,3-disubstituted propan-2-one compounds of AstraZenecacompany are known (Connolly et al, Journal of Medicinal Chemistry, 2002,45, 1348-1362). WO 00/34254 discloses compounds having an inhibitoryeffect on cytosolic phospholipase A₂. Patent specifications U.S. Pat.No. 6,414,179, U.S. 2002/0037875 and U.S. 2002/0065246 disclose alphaamino-substituted, thio-substituted and oxo-substituted ketones as wellas alpha-substituted and beta-substituted trifluoromethylketones asinhibitors of cytosolic phospholipase A₂. Moreover, EP 976 748 disclosescertain pyrrolidine derivatives as inhibitors of cytosolic PhospholipaseA₂.

However, there is still a need for novel compounds which inhibitphospholipase A₂ and in particular cytosolic phospholipase A₂. It hasnow been found surprisingly that certain heteroaryl substituted acetonederivatives solve this problem. The present invention thus relates tocompounds of formula I

wherein

Q represents R¹, OR¹, SR¹, SOR¹, SO₂R¹, NR⁹R¹ or a straight-chain C₁₋₃₁alkyl or C₂₋₃₁ alkenyl or alkynyl residue which may be interrupted by 1or 2 residues, independently selected from O, S, SO, SO₂, NR⁹ and arylwhich may be substituted with 1 or 2 substituents R⁴, and which may besubstituted with 1-4 C₁₋₆ alkyl residues and/or 1 or 2 aryl residues,wherein the aryl residues may be substituted with 1 or 2 substituentsR⁴;

Ar represents an aryl residue which may be substituted with 1 or 2 R⁴substituents;

X represents N or CR⁵;

Y represents N or CR⁶;

R¹ represents H or an aryl residue which may be substituted with 1 or 2R⁴ substituents;

R² and R³

-   a) independently represent H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl    or R⁷—W, or-   b) together with the carbon atoms to which they are bound represent    a 5- or 6-membered aromatic or heteroaromatic ring which may be    substituted with 1 or 2 R⁴ substituents;

R⁴ represents C₁₋₆ alkyl, halogen, CF₃, CN, NO₂, OR⁹, S(O)_(o)R⁹, COR⁹,COOR⁹, CONR⁹R¹⁰, SO₃R⁹, SO₂NR⁹R¹⁰, tetrazolyl or R⁷—W;

R⁵ represents H or R⁴;

R⁶ represents H, C₁₋₆ alkyl, halogen, CF₃, CN, NO₂, OR⁹, SR⁹, COR⁹,COOR⁹, CONR⁹R¹⁰, SO₃R⁹, SO₂NR⁹R¹⁰, tetrazolyl or R⁸—W;

R⁷ represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl;

R⁸ represents C₂₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl;

R⁹ represents H, C₁₋₆ alkyl or aryl;

R¹⁹ represents H or C₁₋₆ alkyl;

W represents COOH, SO₃H or tetrazolyl; and

o is 0, 1 or 2;

and the pharmaceutically compatible salts and esters thereof.

The pharmaceutically compatible salts may be base addition salt. Theycomprise salts of the compounds with inorganic bases, such as alkalihydroxides, alkaline earth hydroxides or with organic bases, such asmono-, di- or triethanolamine. Acid addition salts are also included.

The pharmaceutically compatible esters of the compounds comprise inparticular esters which can easily be hydrolyzed physiologically, e.g.alkyl, pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl andmethoxymethylene esters.

Unless otherwise stated, the expression “alkyl” comprisesstraight-chain, branched or cyclic alkyl groups, such as methyl, ethyl,propyl, butyl, pentyl, neopentyl, undecyl, dodecyl, pentadecyl,hexadecyl, heptadecyl, octadecyl, cyclohexyl, etc.

The expression “alkenyl” comprises straight-chain, branched or cyclicalkenyl groups, such as ethenyl, propenyl, butenyl, decenyl,heptadecenyl, cyclohexenyl, etc.

The term “alkynyl” comprises straight-chain or branched alkynyl groups,such as ethynyl, propynyl, butynyl, decynyl, heptadecynyl, etc.

The term “aryl” comprises phenyl, naphthyl, biphenyl and 5- or6-membered heterocyclic rings, containing 1 to 3 atoms selected from O,N or S and optionally anellated using a benzene ring. Phenyl andindolyl, in particular phenyl, are preferred.

The expression “halogen” comprises a fluorine, chlorine, bromine oriodine atom, the fluorine or chlorine atom being particularly preferred.

If residues such as R⁴, R⁷, R⁹ and/or R¹⁰ occur several times in acompound, they can each be selected independently from one another.

The straight-chain C₁₋₃₁ alkyl or C₂₋₃₁ alkenyl or alkynyl residue,denoted by Q in formula I, can be interrupted by 1 or 2 residues,independently selected from O, S, SO, SO₂, NR⁹ and aryl. “Interrupted”is understood to mean here that in addition to the carbon atoms of itschain the residue may contain such a residue both at any site within thechain and at the end of the chain, i.e. between the carbon chain and Ar.The existing substituents which might additionally be present, whereappropriate, in the form of 1-4 C₁₋₆ alkyl residues and/or 1 or 2 arylresidues may be bound to any carbon atom of the chain.

In the above described compounds of formula I Q preferably denotesR¹—(CHR¹¹)_(p)—A—Z²—B—Z¹—wherein A represents a bond or a straight-chain C_(1-m) alkyl or C_(2-m)alkenyl or alkynyl residue, B represents a bond or a straight-chainC_(1-n) alkyl or C_(2-n) alkenyl or alkynyl residue, R¹ and R¹¹independently represent H or an aryl residue, which may be substitutedwith 1 or 2 substituents R⁴, and Z¹ and Z² independently represent abond, O, S, SO, SO₂, NR⁹, CR⁹R¹⁰ or an aryl residue, wherein the arylresidue may be substituted with 1 or 2 substituents R⁴. p here standsfor 0 or 1, m is an integer from 0 to 12 and n for an integer from 0 to16. The sum of m and n is preferably no greater than 17, in particularno greater than 10.

Q is preferably:R¹—(CHR¹¹)_(p)—(CH₂)_(m)—Z²—(CH₂)_(n)—Z¹—wherein R¹, R¹¹, Z², Z¹, p, m and n are as defined above.

It is particularly preferred to select Q from:R¹—B—Z¹—R¹—CHR¹¹—B—Z¹—R¹—A—Z²—B—Z¹— andR¹—CHR¹¹—A—Z²—B—Z¹—,in particularR¹—(CH₂)_(n)—Z¹—R¹—CHR¹¹—(CH₂)_(n)—Z¹—R¹—(CH₂)_(m)—Z²—(CH₂)_(n)—Z¹— andR¹—CHR¹¹—(CH₂)_(m)—Z²—(CH₂)_(n)—Z¹—.

Preferably R¹ and R¹¹ represent independently from one another, H or aphenyl residue, in particular a non-substituted phenyl residue. Ifdenoting an aryl residue, Z¹ and Z² are preferably phenyl, in particularunsubstituted phenyl.

In a preferred embodiment Q stands for phenyl or C₅₋₁₂ alkyl or alkoxy,more preferably for C₇₋₁₀ alkyl or alkoxy and most preferably for C₈alkyl in den compounds of formula I according to the invention.

In the compounds of formula I according to the invention Ar representsan aryl residue and preferably an aryl residue as defined above. It isparticularly preferred for Ar to represent a phenyl residue whichpreferably links the adjacent groups Q and O in para position.

When R² and R³ together with the carbon atoms to which they are boundform a 5- or 6-membered aromatic or heteroaromatic ring, this ispreferably a benzo ring or a 6-membered aromatic heterocyclic ringhaving 1 to 3 nitrogen atoms. These rings may be substituted with 1 or 2substituents R⁴, an R⁴ substituent and in particular COOH, CH₃, Cl,OCH₃, CN, CHO, COOCH₃ or CONH₂ being preferred.

In the heteroaryl residue of the acetone derivatives according to theinvention, Y preferably denotes CR⁶. R⁵ and R⁶ are preferably selectedfrom H, COOH, t-butyl, Cl, CHO, COCH₃ or COOCH₃.

Particularly suited heteroaryl residues for the acetone derivativesaccording to the invention are pyrrolyl, pyrazolyl, indolyl, indazolyl,pyrrolyl-2-carboxylic acid, pyrrolyl-3-carboxylic acid,indolyl-2-carboxylic acid, indolyl-3-carboxylic acid,indolyl-4-carboxylic acid, indolyl-5-carboxylic acid,indolyl-6-carboxylic acid, 5-methylindolyl, 5-chloroindolyl,5-methoxyindolyl, indolyl-5-carbonitrile, indolyl-5-carbaldehyde,indolyl-5-carboxylic acid methyl ester, 3-tert-butylindolyl-5-carboxylicacid, 3-chloroindolyl-5-carboxylic acid, 3-formylindolyl-5-carboxylicacid, 3-acetylindolyl-5-carboxylic acid,3-methoxycarbonylindolyl-5-carboxylic acid,3-tert-butylindolyl-6-carboxylic acid and indolyl-5-carbamide.

The compounds according to the invention have proved to be potentphospholipase A₂ inhibitors. The compounds are thus usable as drugs forpreventing and treating diseases caused or contributorily caused byproducts or secondary products of this enzyme, such as for treating therheumatoid diseases and for preventing and treating allergically induceddiseases. The compounds according to the invention thus represent interalia effective analgesics, antiphlogistics, antipyretics, antiallergicsand broncholytics and are usable for thrombosis prophylaxis and for theprophylaxis of anaphylactic shock and for treating dermatologic diseasessuch as psoriasis, urticaria, acute and chronic exanthemas of allergicand non-allergic genesis.

Therefore, the present invention also relates to pharmaceuticalpreparations comprising a compound of general formula I or apharmaceutically compatible salt or ester thereof.

The compounds of formula I are particularly suited for the production ofa pharmaceutical preparation for preventing or treating diseases whichare caused or contributorily caused by an increased activity ofphospholipase A₂, preferably of cytosolic phospholipase A₂. These aree.g. diseases selected from inflammations, pain, fever, allergies,asthma, psoriasis, cerebral ischemia, Alzheimer's disease, chronic skindiseases, damage to the skin caused by U.V. radiation, rheumaticdiseases, thrombosis, anaphylactic shock, urticuria, acute and chronicexanthemas and endotoxic shock.

The compounds according to the invention can either be administered asindividual therapeutic substances or as mixtures with other therapeuticactive substances. They can be administered as such but in general theyare given as a pharmaceutical preparation, i.e. as active substancemixtures having suitable pharmaceutical carriers or diluents. Thecompounds or preparations can be administered orally, parenterally, byinhalation, rectally or topically (including dermally, transdermally,buccally and sublingually).

The kind of pharmaceutical preparation and pharmaceutical carrier ordiluent depends on the desired kind of administration. Oral preparationsmay be present as tablets or capsules, for example, also in a retardedform, and may contain conventional excipients, such as binders (e.g.syrup acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone),fillers (e.g. lactose, sugar, corn starch, calcium phosphate, sorbitolor glycine, lubricants (e.g. magnesium stearate, talcum, polyethyleneglycol or silica), disintegrating agents (e.g. starch) or wetting agents(e.g. sodium lauryl sulfate). Oral liquid preparations may be present asaqueous or oily suspensions, solutions, emulsions, syrups, elixirs, orsprays, etc., or may be present as a dry powder for reconstitution withwater or another suitable carrier. Such liquid preparations may containconventional additives, e.g. suspending agents, flavoring agents,diluents, or emulsifiers. For parenteral administration it is possibleto use solutions or suspensions with conventional pharmaceuticalcarriers. For administration by inhalation the compounds may be presentin a powdery, aqueous or partially aqueous solution which can be used asan aerosol. Preparations for topical application may be present e.g. aspharmaceutically compatible powders lotions, ointments, creams, gels oras therapeutic systems which contain therapeutically active amounts ofthe compounds according to the invention.

The necessary dosage depends on the form of pharmaceutical preparationused, on the kind of application, the severity of the symptoms and thespecial subject (human or animal) which is treated. The treatment isusually started with a dose below the optimum dose. Thereafter, the doseis raised until the optimum effect for the given conditions is achieved.In general, the compounds according to the invention are administeredthe best in concentrations by which effective actions can be achievedwithout detrimental or disadvantageous effects occurring. They can beadministered as a single dose or in several doses.

The effectiveness of the compounds according to the invention can bedetermined by the inhibition of cytosolic phospholipase A₂. To this end,cytosolic phospholipase A₂ is stimulated in intact human thrombocyteswith calcium ionophor A23187 so as to trigger the release of arachidonicacid from the membrane phospholipids. In order to prevent themetabolization of the enzyme product arachidonic acid via thecyclooxygenase route and the 12-lipoxygenase route, the dualcyclooxygenase/12-lipoxygenase-inhibitor 5,8,11,14-eicosatetraynoic acidis added. Following purification by means of solid phase extraction, thereleased arachidonic acid is determined by reversed phase-HPLC usingU.V. detection. The inhibition of the enzyme by a test substance followsfrom the ratio of the arachidonic acid amounts formed in the presence orabsence of the test substance. More detailed information on the testsystem is made in Example 10.

The present invention also relates to a method of producing a compoundof formula I, wherein a compound of formula II

or a compound of formula III

is reacted with a compound of formula IV

and the alcohol formed is oxidized to give the desired ketone, whereinQ, Ar, X, Y, R² and R³ are as defined above and Abg stands for a leavinggroup such as halogen, in particular bromine.

The below examples explain the invention without limiting it to theconcrete compounds.

All batches were carried out in a nitrogen protective gas atmosphere.Silica gel 60 of Merck company, Darmstadt, Germany, particle size 63-200μm or 15-40 μm (=flash chromatography), was used for the columnchromatographic purification.

EXAMPLE 1 1-(4-Octylphenoxy)-3-(pyrrol-1-yl)propan-2-one

A. 1-(4-Octylphenoxy)-3-(pyrrol-1-yl)propan-2-ol

0.048 g (1.200 mmol) sodium hydride as 60% dispersion in mineral oil issuspended in 10 ml absolute DMF, stirred at room temperature for 10 minand admixed with 0.077 g (1.15 mmol) pyrrole. Having stirred for onehour, a solution of 0.300 g (1.14 mmol) 2-(4-octylphenoxymethyl)oxirane(Kuliev et al. Uch. Zap. Azerb. Gos. Univ. Ser. Khim Nauk. 1964, 4, 97;Chem. Abstr. 1966, 65, 640c) in 10 ml absolute DMF is added drop-wise.The mixture is stirred for 19 hours, hydrolyzed with a semi-saturatedNaCl solution and extracted four times using diethyl ether. The combinedorganic phases are concentrated to half the volume on the rotaryevaporator and washed three times with saturated NaCl solution. Dryingon sodium sulfate, filtration and reconcentration on the rotaryevaporator leave as a crude product a red oil which is purified onsilica gel by means of column chromatography (flow agent: petroleumether/ethyl acetate 95:5) and yields the product as a yellowish oil.

Yield: 0.229 g (0.695 mmol); 61%

C₂₁H₃₁NO₂ (329.5)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.31 (m, 10H), 1.58 (m,2H), 2.55 (t, J=8 Hz, 2H), 3.83-3.92 (m, 2H), 4.06-4.24 (m, 3H), 6.17(t, J=2 Hz, 2H), 6.70 (t, J=2 Hz, 2H), 6.82 (d, J=9 Hz, 2H), 7.10 (d,J=9 Hz, 2H)

B. 1-(4-Octylphenoxy)-3-(pyrrol-1-yl)propan-2-one

1.24 g (12.1 mmol) acetic anhydride are mixed with 10 ml absolute DMSO,stirred at room temperature for 10 min and added drop-wise to a solutionof 0.100 g (0.304 mmol) 1-(4-octylphenoxy)-3-(pyrrol-1-yl)propan-2-ol in10 ml absolute DMSO. Having stirred for 19 hours, the solution is pouredinto a mixture of 5% sodium hydrogen carbonate solution and saturatedNaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractionswith diethyl ether, combination of the organic phases, concentration tohalf the volume on the rotary evaporator, three wash steps usingsaturated NaCl solution, drying on sodium sulfate, filtration andreconcentration on the rotary evaporator leave a brownish oil which ispurified on silica gel by means of column chromatography (flow agent:petroleum ether/ethyl acetate 97:3) and yields the product as a whitesolid.

Yield: 0.087 g (0.266 mmol); 88%

Mp.: 58-59° C.

C₂₁H₂₉NO₂ (327.5)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.26 (m, 10H), 1.58 (m,2H), 2.56 (t, J=8 Hz, 2H), 4.59 (s, 2H), 4.97 (s, 2H), 6.24 (t, J=2 Hz,2H), 6.61 (t, J=2 Hz, 2H), 6.80 (d, J=9 Hz, 2H), 7.12 (d, J=9 Hz, 2H)

EXAMPLE 2 1-(4-Octylphenoxy)-3-(pyrazol-1-yl)propan-2-one

A. 1-(4-Octylphenoxy)-3-(pyrazol-1-yl)propan-2-ol

0.091 g (3.96 mmol) sodium is mixed with 5 ml absolute THF and with asolution of 0.268 g (3.94 mmol) pyrazole in 15 absolute THF. Havingstirred at room temperature for 2 hours, a solution of 0.690 g (2.63mmol) 2-(4-octylphenoxymethyl)oxirane in 10 ml THF is added drop-wiseand boiled under reflux for 8 hours. The cooled reaction mixture ispoured into semi-saturated NaCl solution and extracted four times usingdiethyl ether. The combined organic phases are concentrated to half thevolume on the rotary evaporator. Washing using a semi-saturated NaClsolution, drying on sodium sulfate, filtration and reconcentration onthe rotary evaporator leave as a crude product a yellow solid which ispurified on silica gel by means of column chromatography (flow agent:petroleum ether/ethyl acetate 85:15) and recrystallized from petroleumether and yields the product as a white solid.

Yield: 0.716 g (2.17 mmol); 82%

Mp.: 88° C.

C₂₀H₃₀N₂O₂ (330.5)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=6 Hz, 3H), 1.28 (m, 10H), 1.58 (m,2H), 2.55 (t, J=8 Hz, 2H), 3.71-3.78 (m, 1H), 3.92-4.02 (m, 2H),4.23-4.48 (m, 3H), 6.27 (t, J=2 Hz, 1H), 6.83 (d, J=9 Hz, 2H), 7.09 (d,J=9 Hz, 2H), 7.45 (d, J=2 Hz, 1H), 7.55 (d, J=2 Hz, 1H)

B. 1-(4-Octylphenoxy)-3-(pyrazol-1-yl)propan-2-one

0.154 g (1.51 mmol) acetic anhydride is mixed with 5 ml absolute DMSO,stirred at room temperature for 10 min and added drop-wise to a solutionof 0.050 g (0.152 mmol) 1-(4-octylphenoxy)-3-(pyrazol-1-yl)propan-2-olin 10 ml absolute DMSO. Having stirred at room temperature for 18 hours,the solution is poured into a mixture of 5% sodium hydrogen carbonatesolution and saturated NaCl solution (1:1, v/v) and hydrolyzed for 10min. Four extractions using diethyl ether, combination of the organicphases, concentration to half the volume on the rotary evaporator, threewash steps with saturated NaCl solution, drying on sodium sulfate,filtration and reconcentration on the rotary evaporator leave as a crudeproduct a yellowish solid which is purified on silica gel by means ofcolumn chromatography (flow agent: petroleum ether/ethyl acetate 90:10)and yields the product as a white solid.

Yield: 0.048 g (0.146 mmol); 96%

Mp.: 85-87° C.

C₂₀H₂₈N₂O₂ (328.5)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.28 (m, 10H), 1.57 (m,2H), 2.55 (t, J=8 Hz, 2H), 4.63 (s, 2H), 5.26 (s, 2H), 6.36 (t, J=2 Hz,1H), 6.81 (d, J=9 Hz, 2H), 7.11 (d, J=9 Hz, 2H), 7.43 (d, J=2 Hz, 1H),7.59 (d, J=2 Hz, 1H)

EXAMPLE 3 1-(Indol-1-yl)-3-(4-octylphenoxy)propan-2-one

A. 1-(Indol-1-yl)-3-(4-octylphenoxy)propan-2-ol

0.048 g (1.20 mmol) sodium hydride as 60% dispersion in mineral oil aresuspended in 10 ml absolute DMF, stirred at room temperature for 10 minand mixed with a solution of 0.134 g (1.14 mmol) indole in 10 mlabsolute DMF. Having stirred for 1½ hours, a solution of 0.300 g (1.14mmol) 2-(4-octylphenoxymethyl)oxirane in 10 ml absolute DMF is addeddrop-wise. The mixture is stirred for 16 hours, hydrolyzed with asemi-saturated NaCl solution and extracted four times using diethylether. The combined organic phases are concentrated to half the volumeon the rotary evaporator and washed three times with saturated NaClsolution. Drying on sodium sulfate, filtration and reconcentration onthe rotary evaporator leave as a crude product an orange oil which ispurified on silica gel by means of column chromatography (flow agent:petroleum ether/ethyl acetate 95:5) and yields the product as a yellowoil.

Yield: 0.356 g (0.938 mmol); 82%

C₂₅H₃₃NO₂ (379.5)

¹H-NMR (CDCl₃): δ (ppm)=0.93 (t, J=7 Hz, 3H), 1.31 (m, 10H), 1.62 (m,2H), 2.44 (s broad, 1H), 2.58 (t, J=8 Hz, 2H), 3.84-3.94 (m, 2H),4.29-4.45 (m, 3H), 6.52 (d, J=3 Hz, 1H), 6.82 (d, J=9 Hz, 2H), 7.11 (d,J=9 Hz, 2H), 7.13-7.15 (m, 2H), 7.20-7.25 (m, 1H), 7.40 (d, J=8 Hz, 1H),7.64 (d, J=8 Hz, 1H)

B. 1-(Indol-1-yl)-3-(4-octylphenoxy)propan-2-one

1.77 g (17.3 mmol) acetic anhydride are mixed with 10 ml absolute DMSO,stirred at room temperature for 10 min and added drop-wise to a solutionof 0.164 g (0.432 mmol) 1-(indol-1-yl)-3-(4-octylphenoxy)propan-2-ol in10 ml absolute DMSO. Having stirred for six hours, the solution ispoured into a mixture of 5% sodium hydrogen carbonate solution andsaturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Fourextractions with diethyl ether, combination of the organic phases,concentration to half the volume on the rotary evaporator, three washsteps with saturated NaCl solution, drying on sodium sulfate, filtrationand reconcentration on the rotary evaporator leave as a crude product ayellow oil which is purified on silica gel by means of columnchromatography (flow agent: petroleum ether/ethyl acetate 95:5) andrecrystallized from petroleum ether and yields the product as a whitesolid.

Yield: 0.106 g (0.281 mmol); 65%

Mp.: 65° C.

C₂₅H₃₁NO₂ (377.5)

¹H-NMR (CDCl₃): δ (ppm)=0.90 (t, J=7 Hz, 3H), 1.30 (m, 10H), 1.59 (m,2H), 2.57 (t, J=8 Hz, 2H), 4.59 (s, 2H), 5.16 (s, 2H), 6.60 (d, J=3 Hz,1H), 6.81 (d, J=9 Hz, 2H), 7.05 (d, J=3 Hz, 1H), 7.12-7.16 (m, 4H),7.19-7.23 (m, 1H), 7.65 (d, J=6 Hz, 1H)

EXAMPLE 4 1-(Indazol-1-yl)-3-(4-octylphenoxy)propan-2-one

A. 1-(Indazol-1-yl)-3-(4-octylphenoxy)propan-2-ol

0.048 g (1.20 mmol) sodium hydride as a 60% dispersion in mineral oil issuspended in 10 ml absolute DMF, stirred at room temperature for 10 minand mixed with a solution of 0.135 g (1.14 mmol) indazole. Havingstirred for 1 hour, a solution of 0.300 g (1.14 mmol)2-(4-octylphenoxymethyl)oxirane in 10 ml absolute DMF is addeddrop-wise. The mixture is stirred for 40 hours, hydrolyzed with asemi-saturated NaCl solution and extracted four times using diethylether. The combined organic phases are concentrated to half the volumeon the rotary evaporator and washed three times with saturated NaClsolution. Drying on sodium sulfate, filtration and reconcentration onthe rotary evaporator leave a white solid which is recrystallized frompetroleum ether/ethyl acetate (80:20).

B. 1-(Indazol-1-yl)-3-(4-octylphenoxy)propan-2-one

1.07 g (10.5 mmol) acetic anhydride are mixed with 10 ml absolute DMSO,stirred at room temperature for 10 min and added drop-wise to a solutionof 0.100 g (0.263 mmol) 1-(indazol-1-yl)-3-(4-octylphenoxy)propan-2-olin 10 ml absolute DMSO. Having stirred for 20 hours, the solution ispoured into a mixture of 5% sodium hydrogen carbonate solution andsaturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Fourextractions using diethyl ether, combination of the organic phases,concentration to half the volume on the rotary evaporator, three washsteps with saturated NaCl solution, drying on sodium sulfate, filtrationand reconcentration on the rotary evaporator leave as a crude product ayellow oil which is purified on silica gel by means of columnchromatography (flow agent: petroleum ether/ethyl acetate 90:10) andyields the product as a white solid.

Yield: 0.062 g (0.164 mmol)

Mp.: 66-67° C.

C₂₄H₃₀N₂O₂ (378.5)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.26 (m, 10H), 1.57 (m,2H), 2.55 (t, J=8 Hz, 2H), 4.63 (s, 2H), 5.46 (s, 2H), 6.79 (d, J=9 Hz,2H), 7.11 (d, J=9 Hz, 2H), 7.16-7.20 (m, 2H), 7.37-7.41 (m, 1H),7.75-7.77 (m, 1H), 8.08 (d, J=1 Hz, 1H)

EXAMPLE 5 1-[3-(4-Octylphenoxy)-2-oxopropyl]pyrrol-2-carboxylic acid

A. 1-Bromo-3-(4-octylphenoxy)propan-2-ol

1.17 g (4.46 mmol) 2-(4-octyl-phenoxymethyl)oxirane are dissolved in 10ml absolute dichloromethane and mixed with 1.34 g (22.3 mmol) silica geland with 1.16 g (13.4 mmol) lithium bromide. The suspension isconcentrated almost to dryness on the rotary evaporator and allowed tostand at room temperature for 3 hours. The reaction batch is mixed withdichloromethane, filtrated on cotton wool and concentrated on the rotaryevaporator. Taking up the suspension in diethyl ether, washing withwater, drying on sodium sulfate, filtration and reconcentration on therotary evaporator yield the product as a yellowish oil.

Yield: 1.52 g (4.42 mmol); 99%

C₁₇H₂₇BrO₂ (343.3)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=6 Hz, 3H), 1.28 (m, 10H), 1.58 (m,2H), 2.55 (t, J=8 Hz, 2H), 3.55-3.71 (m, 2H), 4.04-4.21 (m, 3H), 6.84(d, J=9 Hz, 2H), 7.11 (d, J=9 Hz, 2H)

B. [1-Bromo-3-(4-octylphenoxy)propan-2-yl]acetate

0.41 g (5.18 mmol) absolute pyridine is dissolved in 10 ml absolutedichloromethane, cooled to 0° C. and mixed with 0.41 g (5.22 mmol)acetylchloride, N-aetylpyridiniumchloride precipitating. Having stirredfor 30 minutes, 0.50 g (1.46 mmol) 1-bromo-3-(4-octylphenoxy)propan-2-olis dissolved in 10 ml absolute dichloromethane and added drop-wise. Thereaction batch is stirred for another 3 hours at 0° C., diluted withdichloromethane and washed twice with 5% sodium hydrogen carbonatesolution. The combined aqueous phases are extracted again withdichloromethane and the combined organic phases are washed with water.Following drying on sodium sulfate, filtration, concentration on therotary evaporator and mixing with toluene three times and respectiveconcentration on the rotary evaporator, a yellow oil is obtained as thecrude product, which is purified by means of column chromatography onsilica gel (flow agent: petroleum ether/ethyl acetate 95:5) and yieldsthe product as a yellowish oil.

Yield: 0.56 g (1.45 mmol); 100%

C₁₉H₂₉BrO₃ (385.3)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.28 (m, 10H), 1.59 (m,2H), 2.13 (s, 3H), 2.55 (t, J=8 Hz, 2H), 3.59-3.76 (m, 2H), 4.11-4.18(m, 2H), 5.31 (m, 1H), 6.86 (d, J=9 Hz, 2H), 7.10 (d, J=9 Hz, 2H)

C. tert-Butylpyrrole-2-carboxylate

0.50 g (4.50 mmol) pyrrole-2-carboxylic acid is suspended in 15 mlabsolute benzene and boiled under reflux. A solution of 4.07 g (18.0mmol) 90% N,N-dimethylformamidedi-tert-butylacetal in 15 ml absolutebenzene is added drop-wise within 30 min. Following another heatingunder reflux for 30 minutes and subsequent cooling, the reaction mixtureis diluted with diethyl ether, washed with 5% sodium carbonate solutionand with saturated NaCl solution. Drying on sodium sulfate, filtrationand concentration on the rotary evaporator leave as the crude product areddish solid which purified on silica gel by means of columnchromatography (flow agent: petroleum ether/ethyl acetate 95:5) yieldsthe product as a white solid.

Yield: 0.566 g (3.38 mmol); 75%

Mp.: 87-89° C.

C₉H₁₃NO₂ (167.2)

¹H-NMR (CDCl₃): δ (ppm)=1.57 (s, 9H), 6.23 (m, 1H), 6.84 (m, 1H), 6.91(m, 1H), 9.23 (s, broad, 1H)

D.tert-Butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]pyrrole-2-carboxylate

0.145 g (0.867 mmol) tert-butylpyrrole-2-carboxylate is dissolved in 10ml absolute DMSO, mixed with 0.107 g (0.952 mmol)potassium-tert-butylate and stirred at 110° C. for 15 minutes. Asolution of 0.333 g (0.864 mmol)[1-bromo-3-(4-octylphenoxy)propan-2-yl]acetate in 10 ml absolute DMSO isadded drop-wise. Following heating at 110° C. for 30 minutes andsubsequent cooling, hydrolysis is carried out in saturated NaClsolution. Four extractions with diethyl ether, combination of organicphases, concentration to half the volume on the rotary evaporator, threewash steps with saturated NaCl solution, drying on sodium sulfate,filtration and reconcentration on the rotary evaporator leave as thecrude product a yellow oil which is purified on silica gel by means offlash column chromatography (flow agent: petroleum ether/ethyl acetate80:20) and yields the product as a colorless oil.

Yield: 0.169 g (0.358 mmol); 41%

C₂₈H₄₁NO₅ (471.6)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.28 (m, 10H), 1.55 (s,9H), 1.60 (m, 2H), 2.01 (s, 3H), 2.54 (t, J=8 Hz, 2H), 4.01 (dd, J=11 Hzand J=4 Hz, 1H), 4.13 (dd, J=11 Hz and J=4 Hz, 1H), 4.49 (dd, J=14 Hzand J=8 Hz, 1H), 4.86 (dd, J=14 Hz and J=4 Hz, 1H), 5.43-5.48 (m, 1H),6.07 (dd, J=4 Hz and J=2 Hz, 1H), 6.79-6.83 (m, 3H), 6.88 (dd, J=4 Hzand J=2 Hz, 1H), 7.08 (d, J=9 Hz, 2H)

E.tert-Butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]pyrrole-2-carboxylate

0.150 g (0.318 mmol)tert-butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]pyrrole-2-carboxylateis dissolved in 10 ml absolute methanol, mixed with 1.26 ml (0.630 mmol)of a 0.5M sodium methanolate solution and stirred at room temperaturefor 15 min. Following concentration to half the volume on the rotaryevaporator, the batch is diluted with diethyl ether. Washing of theorganic phase with semi-saturated and with saturated NaCl solution,drying on sodium sulfate, filtration and reconcentration on the rotaryevaporator yield the product as a yellowish oil.

Yield: 0.133 g (0.310 mmol); 98%

C₂₆H₃₉NO₄ (429.6)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.28 (m, 10H), 1.56 (s,9H), 1.60 (m, 2H), 2.55 (t, J=8 Hz, 2H), 3.57 (d, J=4 Hz, 1H), 3.93 (d,J=6 Hz, 2H), 4.30 (m, 1H), 4.46 (dd, J=14 Hz and J=6 Hz, 1H), 4.66 (dd,J=14 Hz and J=4 Hz, 1H), 6.11 (dd, J=4 Hz and J=2 Hz, 1H), 6.84 (m, 3H),6.90 (dd, J=4 Hz and J=2 Hz, 1H), 7.08 (d, J=9 Hz, 2H)

F. tert-Butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]pyrrole-2-carboxylate

1.14 g (11.2 mmol) acetic anhydride are mixed with 10 ml absolute DMSO,stirred at room temperature for 10 min and added drop-wise to a solutionof 0.121 g (0.282 mmol)tert-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]pyrrole-2-carboxylatein 10 ml absolute DMSO. Having stirred for 16 hours, the batch is pouredinto a mixture of 5% sodium hydrogen carbonate solution and saturatedNaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractionswith diethyl ether, combination of the organic phases, concentration tohalf the volume on the rotary evaporator, three wash steps withsaturated NaCl solution, drying on sodium sulfate, filtration andreconcentration on the rotary evaporator leave as a crude product ayellow oil which is purified on silica gel by means of columnchromatography (flow agent: petroleum ether/ethyl acetate 98:2) andyields the product as a yellowish oil.

Yield: 0.096 g (0.225 mmol); 80%

C₂₆H₃₇NO₄ (427.6)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.29 (m, 10H), 1.52 (s,9H), 1.60 (m, 2H), 2.55 (t, J=8 Hz, 2H), 4.73 (s, 2H), 5.29 (s, 2H),6.18 (m, 1H), 6.72 (m, 1H), 6.86 (d, J=8 Hz, 2H), 6.93 (m, 1H), 7.11 (d,J=8 Hz, 2H)

G. 1-[3-(4-Octylphenoxy)-2-oxopropyl]pyrrole-2-carboxylic acid

0.045 g (0.105 mmol)tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]pyrrole-2-carboxylate isdissolved in 10 ml absolute dichloromethane and mixed with 0.900 g (7.89mmol) trifluoroacetic acid. After stirring at room temperature for 1hour, the batch is concentrated to dryness on the rotary evaporator. Twodissolutions in toluene and respective concentration on the rotaryevaporator leave as a crude product a brownish solid which isrecrystallized from methanol and some water drops and yields the productas a beige solid.

Yield: 0.016 g (0.043 mmol); 41%

Mp.: 157° C. (decomp.)

C₂₂H₂₉NO₄ (371.5)

¹H-NMR (DMSO-d₆): δ (ppm)=0.84 (t, J=7 Hz, 3H), 1.24 (m, 10H), 1.50 (s,2H), 2.49 (t, J=8 Hz, 2H), 4.86 (s, 2H), 5.27 (s, 2H), 6.11 (m, 1H),6.81 (m, 1H), 6.83 (d, J=8 Hz, 2H), 7.03 (m, 1H), 7.06 (d, J=8 Hz, 2H)

EXAMPLE 6 1-[3-(4-Octylphenoxy)-2-oxopropyl]pyrrole-3-carboxylic acid

A. tert-Butylpyrrole-3-carboxylate

0.50 g (4.50 mmol) pyrrole-3-carboxylic acid is suspended in 15 mlabsolute benzene and boiled under reflux. A solution 4.07 g (18.0 mmol)90% N,N-dimethylformamidedi-tert-butylacetal in 15 ml absolute benzeneis added drop-wise within 30 min. Following another heating under refluxfor 30 minutes and subsequent cooling, the reaction mixture is dilutedwith diethyl ether, washed with 5% sodium carbonate solution andsaturated NaCl solution. Drying on sodium sulfate, filtration andconcentration on the rotary evaporator leave as a crude product a yellowsolid which is purified on silica gel by means of column chromatography(flow agent: petroleum ether/ethyl acetate 90:10) and yields the productas a white solid.

Yield: 0.433 g (2.59 mmol); 58%

Mp.: 82-84° C.

C₉H₁₃NO₂ (167.2)

¹H-NMR (CDCl₃): δ (ppm)=1.55 (s, 9H), 6.59 (m, 1H), 6.72 (m, 1H), 7.34(m, 1H), 8.75 (s, broad, 1H)

B.tert-Butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]pyrrole-3-carboxylate

0.145 g (0.867 mmol) tert-butylpyrrole-3-carboxylate is dissolved in 10ml absolute DMSO, mixed with 0.107 g (0.952 mmol)potassium-tert-butylate and stirred at 110° C. for 15 min. A solution of0.333 g (0.864 mmol) [1-bromo-3-(4-octylphenoxy)propan-2-yl]acetate in10 ml absolute DMSO is added drop-wise. Following 30 minutes of heatingat 110° C. and subsequent cooling, hydrolysis is carried out insaturated NaCl solution. Four extractions with diethyl ether,combination of the organic phases, concentration to half the volume onthe rotary evaporator, three wash steps using saturated NaCl solution,drying on sodium sulfate, filtration and reconcentration on the rotaryevaporator leave as a crude product a yellow oil which is purified onsilica gel by means of flash column chromatography (flow agent:petroleum ether/ethyl acetate 93:7) and yields the product as acolorless oil.

Yield: 0.104 g (0.221 mmol); 26%

C₂₈H₄₁NO₅ (471.6)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.26 (m, 10H), 1.52 (s,9H), 1.59 (m, 2H), 2.09 (s, 3H), 2.54 (t, J=8 Hz, 2H), 3.89 (dd, J=10 Hzand J=6 Hz, 1H), 3.95 (dd, J=10 Hz and J=4 Hz, 1H), 3.89-4.25 (m, 2H),5.30 (m, 1H), 6.50 (dd, J=3 Hz and J=2 Hz, 1H), 6.57 (m, 1H), 6.81 (d,J=9 Hz, 2H), 7.09 (d, J=9 Hz, 2H), 7.20 (m, 1H)

C.tert-Butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]pyrrole-3-carboxylate

0.104 g (0.221 mmol)tert-butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]pyrrole-3-carboxylateis dissolved in 10 ml absolute methanol, mixed with 0.88 ml (0.440 mmol)of a 0.5M sodium methanolate solution and stirred at room temperaturefor 15 min. Following concentration to half the volume on the rotaryevaporator, the batch is diluted with diethyl ether. Washing of theorganic phase with semi-saturated and with saturated NaCl solution,drying on sodium sulfate, filtration and reconcentration on the rotaryevaporator yield the product as a yellowish oil.

Yield: 0.091 g (0.212 mmol); 96%

C₂₆H₃₉NO₄ (429.6)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.30 (m, 10H), 1.55 (s,9H), 1.62 (m, 2H), 2.46 (s broad, 1H), 2.54 (t, J=8 Hz, 2H), 3.86 (dd,J=10 Hz and J=6 Hz), 3.92 (dd, J=9 Hz and J=5 Hz), 4.07 (dd, J=14 Hz andJ=7 Hz), 4.16 (dd, J=14 Hz and J=5 Hz), 4.27 (m, 1H), 6.55 (dd, J=3 Hzand J=2 Hz, 1H), 6.63 (m, 1H), 6.82 (d, J=9 Hz, 2H), 7.11 (d, J=9 Hz,2H), 7.27 (m, 1H)

D. tert-Butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]pyrrole-3-carboxylate

0.817 g (8.00 mmol) acetic anhydride is mixed with 10 ml absolute DMSO,stirred at room temperature for 10 min and added drop-wise to a solutionof 0.086 g (0.200 mmol)tert-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]pyrrole-3-carboxylatein 10 ml absolute DMSO. Having stirred for 19 hours, the solution ispoured into a mixture of 5% sodium hydrogen carbonate solution andsaturated NaCl solution (1:1, v/v) and hydrolyzed for 10 min. Fourextractions using diethyl ether, combination of the organic phases,concentration to half the volume on the rotary evaporator, three washsteps with saturated NaCl solution, drying on sodium sulfate, filtrationand reconcentration on the rotary evaporator leave as a crude product abrown oil which is purified on silica gel by means of flash columnchromatography (flow agent: petroleum ether/ethyl acetate 90:10) andyields the product as a yellowish oil.

Yield: 0.065 g (0.152 mmol); 76%

C₂₆H₃₇NO₄ (427.6)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.26 (m, 10H), 1.53 (s,9H), 1.59 (m, 2H), 2.56 (t, J=8 Hz, 2H), 4.63 (s, 2H), 4.99 (s, 2H),6.50 (m, 1H), 6.59 (dd, J=3 Hz and J=2 Hz, 1H), 6.82 (d, J=9 Hz, 2H),7.13 (m, 3H)

E. 1-[3-(4-Octylphenoxy)-2-oxopropyl]pyrrole-3-carboxylic acid

0.049 g (0.115 mmol)tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]pyrrole-3-carboxylate isdissolved in 10 ml absolute dichloromethane and mixed with 0.988 g (8.67mmol) tifluoroacetic acid. Having stirred at room temperature for 3½hours, the batch is concentrated to dryness on the rotary evaporator.Two dissolution steps in toluene and respective concentrations on therotary evaporator leave as a crude product a greenish solid which issolved in diethyl ether and precipitated with petroleum ether. Twentyminutes of centrifugation at 3000 rpm, decantation of the supernatant,displacement of the solvent residues in the nitrogen flow and drying ina vacuum desiccator yield the product as a beige solid.

Yield: 0.018 g (0.048 mmol); 42%

Mp.: 125° C. (decomp.)

C₂₂H₂₉NO₄ (371.5)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.28 (m, 10H), 1.57 (m,2H), 2.56 (t, J=8 Hz, 2H), 4.65 (s, 2H), 5.04 (s, 2H), 6.55 (m, 1H),6.68 (m, 1H), 6.82 (d, J=8 Hz, 2H), 7.14 (d, J=8 Hz, 2H), 7.30 (m, 1H)

EXAMPLE 7 1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-2-carboxylic acid

A. tert-Butylindole-2-carboxylate

1.00 g (6.21 mmol) indole-2-carboxylic acid is dissolved in 15 mlabsolute THF, mixed with 1.01 g (6.23 mmol) N,N-carbonyldiimidazole andstirred at room temperature for 1 hour. Thereafter, 0.77 g (6.86 mmol)potassium-tert-butylate and 9.12 g (123 mmol) tert-butanol are added.Following heating under reflux for 6 hours, quenching using 5 ml water,filtrating off, rinsing with THF, drying on sodium sulfate andconcentration on the rotary evaporator, a brown solid is obtained as thecrude product. Preliminary purification by means of columnchromatography on silica gel using a short column with petroleumether/ethyl acetate 95:5 leaves a white solid which is purified onsilica gel by means of column chromatography (flow agent: petroleumether/ethyl acetate 98:2) and yields the product as a white solid.

Yield: 0.325 g (1.496 mmol); 24%

Mp.: 104-105° C.

C₁₃H₁₅NO₂ (217.3)

¹H-NMR (CDCl₃): δ (ppm)=1.65 (s, 9H), 7.14 (m, 2H), 7.31 (m, 1H), 7.43(dd, J=8 Hz and J=1 Hz, 1H), 7.68 (dd, J=8 Hz and J=1 Hz, 1H), 9.12 (s,broad, 1H)

B. tert-Butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]indole-2-carboxylate

0.325 g (1.50 mmol) tert-butylindole-2-carboxylate is dissolved in 15 mlabsolute DMSO, mixed with 0.184 g (1.64 mmol) potassium-tert-butylateand stirred at 110° C. for 15 min. A solution of 0.576 g (1.50 mmol)[1-bromo-3-(4-octylphenoxy)propan-2-yl]acetate in 15 ml absolute DMSO isadded drop-wise. Following 30 minutes of heating at 110° C. andsubsequent cooling, hydrolysis is carried out in saturated NaClsolution. Four extractions with diethyl ether, combination of theorganic phases, concentration to half the volume on the rotaryevaporator, three wash steps with saturated NaCl solution, drying onsodium sulfate, filtration and reconcentration on the rotary evaporatorleave as a crude product a yellow oil which is purified on silica gel bymeans of flash column chromatography (flow agent: petroleum ether/ethylacetate 99:1) and yields the product as a colorless oil.

Yield: 0.246 g (0.472 mmol); 32%

C₃₂H₄₃NO₅ (521.7)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.30 (m, 10H), 1.59 (m,2H), 1.62 (s, 9H), 1.81 (s, 3H), 2.56 (t, J=8 Hz, 2H), 4.17 (d, J=4 Hz,2H), 4.83 (dd, J=15 Hz and J=8 Hz, 1H), 5.07 (dd, J=15 Hz and J=5 Hz,1H), 5.57 (m, 1H), 6.84 (d, J=9 Hz, 2H), 7.09 (d, J=9 Hz, 2H), 7.13 (m,1H), 7.26 (s, 1H), 7.32 (m, 1H), 7.57 (d, J=8 Hz, 1H), 7.64 (d, J=8 Hz,1H)

C. tert-Butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-2-carboxylate

0.213 g (0.408 mmol)tert-butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]indole-2-carboxylate isdissolved in 10 ml absolute methanol, mixed with 1.64 ml (0.82 mmol) ofa 0.5M sodium methanolate solution and stirred at room temperature for15 min. Following concentration to half the volume on the rotaryevaporator, the batch is diluted with diethyl ether. Washing of theorganic phase with semi-saturated and with saturated NaCl solution,drying on sodium sulfate, filtration and reconcentration on the rotaryevaporator leave as a crude product a yellowish oil which is purified onsilica gel by means of column chromatography (flow agent: petroleumether/ethyl acetate 95:5) and yields the product as a yellowish oil.

Yield: 0.152 g (0.317 mmol); 78%

C₃₀H₄₁NO₄ (479.7)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.29 (m, 10H), 1.59 (m,2H), 1.63 (s, 9H), 2.55 (t, J=8 Hz, 2H), 3.62 (s broad, 1H), 3.99 (dd,J=10 Hz and J=6 Hz, 1H), 4.04 (dd, J=10 Hz and J=5 Hz, 1H), 4.42 (m,1H), 4.76 (dd, J=15 Hz and J=7 Hz, 1H), 4.81 (dd, J=15 Hz and J=5 Hz,1H), 6.86 (d, J=9 Hz, 2H), 7.10 (d, J=9 Hz, 2H), 7.14 (m, 1H), 7.29 (m,2H), 7.48 (d, J=8 Hz, 1H), 7.69 (d, J=8 Hz, 1H)

D. tert-Butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-2-carboxylate

1.02 g (10.0 mmol) acetic anhydride are mixed with 10 ml absolute DMSO,stirred at room temperature for 10 min and added drop-wise to a solutionof 0.120 g (0.250 mmol)tert-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-2-carboxylate in10 ml absolute DMSO. Having stirred for 8 hours, the solution is pouredinto a mixture of 5% sodium hydrogen carbonate solution and saturatedNaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractionswith diethyl ether, combination of the organic phases, concentration tohalf the volume on the rotary evaporator, three wash steps usingsaturated NaCl solution, drying on sodium sulfate, filtration andreconcentration on the rotary evaporator leave as a crude product ayellow oil which is purified on silica gel by means of columnchromatography (flow agent: petroleum ether/ethyl acetate 98:2) andyields the product as a yellowish oil.

Yield: 0.113 g (0.237 mmol); 95%

C₃₀H₃₉NO₄ (477.6)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.29 (m, 10H), 1.58 (s,9H), 1.61 (m, 2H), 2.57 (t, J=8 Hz, 2H), 4.73 (s, 2H), 5.57 (s, 2H),6.87 (d, J=9 Hz, 2H), 7.11-7.14 (m, 4H), 7.30 (m, 2H), 7.68 (d, J=8 Hz,1H)

E. 1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-2-carboxylic acid

0.046 g (0.096 mmol)tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-2-carboxylate isdissolved in 10 ml absolute dichloromethane and mixed with 1.49 g (13.6mmol) trifluoroacetic acid. Having stirred at room temperature for 1½hours, concentration to dryness is carried out on the rotary evaporator.Two dissolution steps in toluene and respective concentration on therotary evaporator leave as a crude product a yellowish solid which isrecrystallized from petroleum ether/ethyl acetate (67:33) and yields theproduct as a white solid.

Yield: 0.031 g (0.074 mmol); 77%

Mp.: 173° C.

C₂₆H₃₁NO₄ (421.5)

¹H-NMR (DMSO-d₆): δ (ppm)=0.83 (t, J=7 Hz, 3H), 1.23 (m, 10H), 1.50 (m,2H), 2.48 (t, J=8 Hz, 2H), 4.99 (s, 2H), 5.60 (s, 2H), 6.86 (d, J=9 Hz,2H), 7.07 (d, J=9 Hz, 2H), 7.12 (m, 1H), 7.26 (s, 1H), 7.29 (m, 1H),7.54 (d, J=8 Hz, 1H), 7.68 (d, J=8 Hz, 1H)

EXAMPLE 8 1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-3-carboxylic acid

A. tert-Butylindole-3-carboxylate

1.00 g (6.21 mmol) indole-3-carboxylic acid is dissolved in 150 mlabsolute THF, mixed with 0.05 g (0.68 mmol) absolute DMF as well as with1.48 g (12.5 mmol) thionylchloride and stirred at room temperature for 1hour. Following the drop-wise addition of 2.51 g (24.8 mmol)tiethylamine and of 9.20 g (124 mmol) tert-butanol and heating underreflux for 2 hours, hydrolysis of the cooled reaction mixture is carriedout in water. Three extractions with diethyl ether, concentration tohalf the volume on the rotary evaporator, washing with 5% sodiumcarbonate solution and with saturated NaCl solution, drying on sodiumsulfate, filtration and reconcentration on the rotary evaporator leaveas a crude product a brown oil which is purified on silica gel by meansof column chromatography (flow agent: petroleum ether/ethyl acetate90:10) and yields the product as a yellow oil.

Yield: 1.05 g (4.83 mmol); 78%

C₁₃H₁₅NO₂ (217.3)

¹H-NMR (CDCl₃): δ (ppm)=1.65 (s, 9H), 7.25 (m, 2H), 7.39 (m, 1H), 7.85(d, J=3 Hz, 1H), 8.15 (m, 1H), 8.84 (s, broad, 1H)

B. tert-Butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]indole-3-carboxylate

0.50 g (2.30 mmol) tert-butylindole-3-carboxylate is dissolved in 15 mlabsolute DMSO, mixed with 0.28 g (2.50 mmol) potassium-tert-butylate andstirred at 110° C. for 15 min. A solution of 0.89 g (2.31 mmol)[1-bromo-3-(4-octylphenoxy)propan-2-yl]acetate in 15 ml absolute DMSO isadded drop-wise. Following heating at 110° C. for 30 minutes andsubsequent cooling, hydrolysis is carried out in saturated NaClsolution. Four extractions with diethyl ether, combination of theorganic phases, concentration to half the volume on the rotaryevaporator, three wash steps with saturated NaCl solution, drying onsodium sulfate, filtration and reconcentration on the rotary evaporatorleave as a crude product a yellow oil which is purified on silica gel bymeans of flash column chromatography (flow agent: petroleum ether/ethylacetate 95:5) and yields the product as a yellowish oil.

Yield: 0.56 g (1.07 mmol); 47%

C₃₂H₄₃NO₅ (521.7)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.29 (m, 10H), 1.57 (m,2H), 1.61 (s, 9H), 2.05 (s, 3H), 2.55 (t, J=8 Hz, 2H), 3.97 (d, J=5 Hz,2H), 4.51 (dd, J=9 Hz and J=6 Hz, 1H), 4.56 (dd, J=9 Hz and J=6 Hz, 1H),5.43 (m, 1H), 6.83 (d, J=9 Hz, 2H), 7.10 (d, J=9 Hz, 2H), 7.24 (m, 2H),7.45 (m, 1H), 7.75 (s, 1H), 8.14 (m, 1H)

C. tert-Butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-3-carboxylate

0.293 g (0.562 mmol)tert-butyl-1-[2-acetoxy-3-(4-octylphenoxy)propyl]indole-3-carboxylate isdissolved in 20 ml absolute methanol, mixed with 2.24 ml (1.12 mmol) ofa 0.5M sodium methanolate solution and stirred at room temperature for15 min. Following concentration to half the volume on the rotaryevaporator, the batch is diluted with diethyl ether. Washing of theorganic phase with semi-saturated and with saturated NaCl solution,drying on sodium sulfate, filtration and reconcentration on the rotaryevaporator yield the product as a yellowish oil.

Yield: 0.269 g (0.561 mmol); 100%

C₃₀H₄₁NO₄ (479.7)

¹H-NMR (CDCl₃): δ (ppm)=0.90 (t, J=7 Hz, 3H), 1.30 (m, 10H), 1.59 (m,2H), 1.63 (s, 9H), 2.56 (t, J=8 Hz, 2H), 2.66 (s, broad, 1H), 3.89 (dd,J=10 Hz and J=5 Hz, 1H), 3.95 (dd, J=10 Hz and J=5 Hz, 1H), 4.30 (dd,J=14 Hz and J=6 Hz, 1H), 4.37 (m, 1H), 4.45 (dd, J=14 Hz and J=4 Hz,1H), 6.81 (d, J=8 Hz, 2H), 7.09 (d, J=8 Hz, 2H), 7.25 (m, 2H), 7.40 (m,1H), 7.98 (s, 1H), 8.16 (m, 1H)

D. tert-Butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-3-carboxylate

2.02 g (19.8 mmol) acetic anhydride are mixed with 10 ml absolute DMSO,stirred at room temperature for 10 min and added drop-wise to a solutionof 0.237 g (0.494 mmol)tert-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-3-carboxylate in10 ml absolute DMSO. Having stirred for 2 hours, the solution is pouredinto a mixture of 5% sodium hydrogen carbonate and saturated NaClsolution (1:1, v/v) and hydrolyzed for 10 min. Four extractions withdiethyl ether, combination of the organic phases, concentration to halfthe volume on the rotary evaporator, three wash steps with saturatedNaCl solution, drying on sodium sulfate, filtration and reconcentrationon the rotary evaporator leave as a crude product a yellow oil which ispurified on silica gel by means of flash column chromatography (flowagent: petroleum ether/ethyl acetate 95:5) and yields the product as ayellowish oil.

Yield: 0.160 g (0.335 mmol); 68%

C₃₀H₃₉NO₄ (477.6)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.30 (m, 10H), 1.59 (m,2H), 1.62 (s, 9H), 2.58 (t, J=8 Hz, 2H), 4.66 (s, 2H), 5.22 (s, 2H),6.85 (d, J=9 Hz, 2H), 7.08 (dd, J=7 Hz and J=2 Hz, 1H), 7.15 (d, J=9 Hz,2H), 7.24 (m, 2H), 7.71 (s, 1H), 8.17 (dd, J=6 Hz and J=2 Hz, 1H)

E. 1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-3-carboxylic acid

0.072 g (0.151 mmol)tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-3-carboxylate isdissolved in 10 ml absolute dichloromethane and mixed with 1.56 g (13.7mmol) trifluoroacetic acid. Having stirred at room temperature for 1hour, concentration to dryness is carried out on the rotary evaporator.Two dissolution steps in toluene and respective concentration on therotary evaporator leave as the crude product a reddish solid which isrecrystallized from petroleum ether/ethyl acetate (67:33) and yields theproduct as a white solid.

Yield: 0.055 g (0.130 mmol); 86%

Mp.: 182-183° C.

C₂₆H₃₁NO₄ (421.5)

¹H-NMR (DMSO-d₆): δ (ppm)=0.84 (t, J=7 Hz, 3H), 1.24 (m, 10H), 1.51 (m,2H), 2.49 (t, J=8 Hz, 2H), 5.00 (s, 2H), 5.46 (s, 2H), 6.88 (d, J=9 Hz,2H), 7.10 (d, J=9 Hz, 2H), 7.18 (m, 2H), 7.44 (m, 1H), 7.97 (s, 1H),8.00 (m, 1H)

EXAMPLE 9 1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid

A. tert-Butylindole-5-carboxylate

0.50 g (3.10 mmol) indole-5-carboxylic acid is suspended in 20 mlabsolute benzene and heated under reflux. A solution of 2.80 g (12.39mmol) 90% N,N-dimethylformamidedi-tert-butylacetal in 20 ml absolutebenzene is added drop-wise within 30 min. Following another heatingunder reflux for 30 minutes and subsequent cooling, the reaction mixtureis diluted with diethyl ether, washed with 5% sodium carbonate solutionand with saturated NaCl solution. Drying on sodium sulfate, filtrationand concentration on the rotary evaporator leave as a crude product ayellow oil which is purified on silica gel by means of columnchromatography (flow agent: petroleum ether/ethyl acetate 95:5) andyields the product as a white solid.

Yield: 0.214 g (0.98 mmol); 32%

Mp.: 91-93° C.

C₁₃H₁₅NO₂ (217.3)

¹H-NMR (CDCl₃): δ (ppm)=1.63 (s, 9H), 6.64 (m, 1H), 7.26 (m, 1H), 7.38(d, J=9 Hz, 1H), 7.87 (dd, 1H, J=9 Hz and J=2 Hz), 8.36 (m, 1H), 8.40(s, broad, 1H)

B. tert-Butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylate

0.077 g (1.93 mmol) sodium hydride as a 60% dispersion in mineral oil issuspended in 15 ml absolute DMF, stirred at room temperature for 10 min,mixed with a solution of 0.400 g (1.84 mmol)tert-butylindole-5-carboxylate in 15 ml absolute DMF and stirred at roomtemperature for one hour. A solution of 0.483 g (1.84 mmol)2-(4-octyl-phenoxymethyl)oxirane in 15 ml absolute DMF is addeddrop-wise. Following four hours of heating at 60° C. and subsequentcooling, hydrolysis is carried out in a semi-saturated NaCl solution.Four extractions with diethyl ether, combination of the organic phases,concentration to half the volume on the rotary evaporator, three washsteps with saturated NaCl solution, drying on sodium sulfate, filtrationand reconcentration on the rotary evaporator leave as a crude product ayellow oil which is purified on silica gel by means of flash columnchromatography (flow agent: petroleum ether/ethyl acetate 90:10) andyields the product as a colorless oil.

Yield: 0.765 g (1.60 mmol); 87%

C₃₀H₄₁NO₄ (479.7)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.29 (m, 10H), 1.58 (m,2H), 1.62 (s, 9H), 2.55 (t, J=8 Hz, 2H), 3.83 (dd, J=10 Hz and J=5 Hz,1H), 3.93 (dd, J=10 Hz and J=4 Hz, 1H), 4.33 (m, 2H), 4.42 (m, 1H), 6.60(dd, J=3 Hz and J=1 Hz, 1H), 6.80 (d, J=9 Hz, 2H), 7.08 (d, J=9 Hz, 2H),7.20 (d, J=3 Hz, 1H), 7.37 (d, J=9 Hz, 1H), 7.86 (dd, J=9 Hz and J=2 Hz,1H), 8.33 (d, J=2 Hz, 1H)

C. tert-Butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylate

5.33 g (52.2 mmol) acetic anhydride are mixed with 30 ml absolute DMSO,stirred at room temperature for 10 min and added drop-wise to a solutionof 0.626 g (1.31 mmol)tert-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylate in20 ml absolute DMSO. Having stirred for 17 hours, the solution is pouredinto a mixture of 5% sodium hydrogen carbonate solution and saturatedNaCl solution (1:1, v/v) and hydrolyzed for 10 min. Four extractionsusing diethyl ether, combination of the organic phases, concentration tohalf the volume on the rotary evaporator, three wash steps withsaturated NaCl solution, drying on sodium sulfate, filtration andreconcentration on the rotary evaporator leave as a crude product ayellow oil which is purified on silica gel by means of flash columnchromatography (flow agent: petroleum ether/ethyl acetate 95:5) andyields the product as a colorless oil.

Yield: 0.232 g (0.486 mmol); 37%

C₃₀H₃₉NO₄ (477.6)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.30 (m, 10H), 1.61 (m,2H), 1.63 (s, 9H), 2.59 (t, J=8 Hz, 2H), 4.64 (s, 2H), 5.21 (s, 2H),6.68 (dd, J=3 Hz and J=1 Hz, 1H), 6.84 (d, J=9 Hz, 2H), 7.09 (d, J=9 Hz,1H and d, J=3 Hz, 1H), 7.15 (d, J=9 Hz, 2H), 7.87 (dd, J=9 Hz and J=2Hz, 1H), 8.35 (dd, J=2 Hz and J=1 Hz, 1H)

D. 1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid

0.222 g (0.465 mmol)tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylate isdissolved in 60 ml absolute dichloromethane and mixed with 3.98 g (34.9mmol) trifluoroacetic acid. Having stirred at room temperature for 4hours, concentration to dryness is carried out on the rotary evaporator.Two admixtures with hexane and respective concentration to dryness onthe rotary evaporator leave as a crude product a brownish solid which ispurified on an RP-HPLC column by means of chromatography (stationaryphase: cromasil, mobile phase acetonitrile/water 80:20) and yields theproduct as a white solid.

Yield: 0.134 g (0.318 mmol); 68%

Mp.: 122-124° C.

C₂₆H₃₁NO₄ (421.5)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.29 (m, 10H), 1.59 (m,2H), 2.58 (t, J=8 Hz, 2H), 4.66 (s, 2H), 5.25 (s, 2H), 6.71 (d, J=3 Hz,1H), 6.85 (d, J=8 Hz, 2H), 7.14 (m, 4H), 7.96 (d, J=9 Hz, 1H), 8.49 (s,1H)

EXAMPLE 10 1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-4-carbocylic acid A.tert-Butylindol-4-carboxylate

The preparation is based on indol-4-carboxylic acid in analogy to thesynthesis of step A of Example 9.

Mp.: 96° C.

C₁₃H₁₅NO₂ (217.3)

¹H-NMR (CDCl₃): δ (ppm)=1.68 (s, 9H), 7.17-7.19 (m, 1H), 7.21-7.25 (m,1H), 7.33-7.34 (m, 1H), 7.57 (d, J=8 Hz, 1H), 7.88 (dd, J=8 Hz and J=1Hz, 1H), 8.39 (s, broad, 1H)

B. tert-Butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-4-carboxylate

The preparation is based on tert-butylindole-4-carboxylate in analogy tothe synthesis of step B of Example 9. Deviating therefrom, the reactiontime is only 3 h. Chromatographic purification is initially carried outon silica gel (flow agent petroleum ether/ethyl acetate 85:15) and thenon RP18 material (flow agent acetonitrile/water 80:20). The productaccrues as an oil.

C₃₀H₄₁NO₄ (479.7)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.27-1.31 (m, 10H),1.56-1.64 (m, 2H), 1.67 (s, 9H), 2.38 (s, broad, 1H), 2.55 (t, J=8 Hz,2H), 3.83 (dd, J=9 Hz and J=5 Hz, 1H), 3.92 (dd, J=9 Hz and J=5 Hz, 1H),4.34-4.38 (m, 2H), 4.47 (dd, J=17 Hz and J=8 Hz, 1H), 6.79 (d, J=9 Hz,2H), 7.08 (d, J=8 Hz, 2H), 7.13 (d, J=3 Hz, 1H), 7.20-7.24 (m, 1H), 7.27(d, J=3 Hz, 1H), 7.57 (dd, J=8 Hz and J=1 Hz, 1H), 7.86 (d, J=7 Hz, 1H)

C. tert-Butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-4-carboxylate

The preparation is based ontert-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-4-carboxylate inanalogy to the synthesis of step C of Example 9. Deviating therefrom,the reaction time is only 15 h. The chromatographic purification iscarried out on silica gel (flow agent petroleum ether/ethyl acetate93:7). The product accrues as a solid.

Mp.: 100° C.

C₃₀H₃₉NO₄ (477.6)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.27-1.31 (m, 10H),1.56-1.60 (m, 2H), 1.67 (s, 9H), 2.57 (t, J=8 Hz, 2H), 4.61 (s, 2H),5.22 (s, 2H), 6.82 (d, J=9 Hz, 2H), 7.14 (d, J=9 Hz, 2H), 7.16 (d, J=3Hz, 1H), 7.20-7.22 (m, 2H), 7.24-7.28 (m, 1H), 7.88 (dd, J=7 Hz and J=1Hz, 1H)

D. 1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-4-carboxylic acid

63 mg (0.13 mmol) ketone are dissolved in 15 ml absolute dichloromethaneand mixed with 1.12 g (9.82 mmol) trifluoroacetic acid. Stirring at roomtemperature for 2 hours is followed by concentration to dryness on therotary evaporator. Three admixtures with 10 ml of a mixture of petroleumether and ethyl acetate (1:2) each and respective concentration todryness on the rotary evaporator leave as a crude product a solid whichis recrystallized from petroleum ether/ethyl acetate (2:1).

Yield: 48 mg (0.11 mmol); 86%

Mp.: 160-161° C.

C₂₆H₃₁NO₄ (421.5)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.28-1.32 (m, 10H),1.56-1.63 (m, 2H), 2.58 (t, J=8 Hz, 2H), 4.64 (s, 2H), 5.26 (s, 2H),6.84 (d, J=9 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 7.22 (d, 1H), 7.25-7.29 (m,1H), 7.31 (d, J=3 Hz, 1H), 7.35 (d, J=8 Hz, 1H), 8.02 (d, J=7 Hz, 1H)

EXAMPLE 11 1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-6-carboxylic acid A.tert-Butylindole-6-carboxylate

The preparation is based on indole-6-carboxylic acid in analogy to thesynthesis of step A of Example 9. The product is additionallyrecrystallized from petroleum ether.

Mp.: 100-101° C.

C₁₃H₁₅NO₂ (217.3)

¹H-NMR (CDCl₃): δ (ppm)=1.63 (s, 9H), 6.59 (m, 1H), 7.35 (m, 1H), 7.63(d, J=8 Hz, 1H), 7.77 (dd, J=8 Hz and J=1 Hz, 1H), 8.13 (m, 1H), 8.55(s, broad, 1H)

B. tert-Butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-6-carboxylate

The preparation is based on tert-butylindole-6-carboxylate in analogy tothe synthesis of step B of Example 9. Deviating therefrom, the reactiontime is 5 h. The chromatographic purification is initially carried outon silica gel (flow agent: petroleum ether/ethyl acetate 9:1) and thenon RP18 material (flow agent acetonitrile/water 4:1). The productaccrues as an oil.

C₃₀H₄₁NO₄ (479.7)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.26-1.30 (m, 10H),1.56-1.60 (m, 2H), 1.62 (s, 9H), 2.45 (s, broad, 1H), 2.54 (t, J=8 Hz,2H), 3.84 (dd, J=10 Hz and J=5 Hz, 1H), 3.93 (dd, J=10 Hz and J=4 Hz,1H), 4.33-4.37 (m, 2H), 4.48 (dd, J=17 Hz and J=8 Hz, 1H), 6.54 (dd, J=3Hz and J=1 Hz, 1H), 6.80 (d, J=9 Hz, 2H), 7.08 (d, J=9 Hz, 2H), 7.30 (d,J=3 Hz, 1H), 7.61 (d, J=8 Hz, 1H), 7.75 (dd, J=8 Hz and J=1 Hz, 1H),8.11 (m, 1H)

C. tert-Butyl-1-[³-(4-octylphenoxy)-2-oxopropyl]indole-6-carboxylate

The preparation is based ontert-butyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-6-carboxylate inanalogy to the synthesis of step C of Example 9. Deviating therefrom,the reaction time is only 16 h. The product accrues as an oil.

C₃₀H₃₉NO₄ (477.6)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.27-1.31 (m, 10H),1.57-1.62 (m, 2H), 1.62 (s, 9H), 2.57 (t, J=8 Hz, 2H), 4.64 (s, 2H),5.28 (s, 2H), 6.62 (dd, J=3 Hz and J=1 Hz, 1H), 6.84 (d, J=8 Hz, 2H),7.14 (d, J=8 Hz, 2H), 7.16 (d, J=3 Hz, 1H), 7.63 (dd, J=8 Hz and J=1 Hz,1H), 7.74 (dd, J=8 Hz and J=1 Hz, 1H), 7.89 (m, 1H)

D. 1-[³-(4-Octylphenoxy)-2-oxopropyl]indole-6-carboxylic acid

59 mg (0.12 mmol)tert-butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-6-carboxylate aredissolved in 15 ml absolute dichloromethane and mixed with 1.05 g (9.20mmol) trifluoroacetic acid. After stirring at room temperature for 2½hours, concentration to dryness is carried out on the rotary evaporator.Three admixtures with 10 ml of a mixture of petroleum ether and ethylacetate (1:2) each and respective concentration to dryness on the rotaryevaporator leave as a crude product a solid which is purified on anRP-HPLC column (stationary phase: cromasil, mobile phase:acetonitrile/water 9:1) by means of chromatography.

Yield: 30 mg (0.07 mmol); 57%

Mp.: 180° C.

C₂₆H₃₁NO₄ (421.5)

¹H-NMR (DMSO-d₆): δ (ppm) 0.83 (t, J=7 Hz, 3H), 1.21-1.27 (m, 10H),1.48-1.62 (m, 2H), 2.48 (t, J=8 Hz, 2H), 5.00 (s, 2H), 5.48 (s, 2H),6.55 (dd, J=3 Hz and J=1 Hz, 1H), 6.86 (d, J=9 Hz, 2H), 7.08 (d, J=9 Hz,2H), 7.46 (d, J=3 Hz, 1H), 7.58-7.62 (m, 2H), 8.06 (d, J=1 Hz, 1H)

EXAMPLE 12 1-(5-Methylindol-1-yl)-3-(4-octylphenoxy)propan-2-one A.1-(5-Methylindole-1-yl)-3-(4-octylphenoxy)propan-2-ol

The preparation is based on 5-methylindole in analogy to the synthesisof step B of Example 9. Deviating therefrom, the reaction is carried outat room temperature. The reaction time is 23 h. The chromatographicpurification is carried out on silica gel (flow agent: petroleumether/ethyl acetate 95:5). The product accrues as an oil.

C₂₆H₃₅NO₂ (393.6)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.27-1.31 (m, 10H),1.54-1.58 (m, 2H), 2.36 (s, broad, 1H), 2.45 (s, 3H), 2.55 (t, J=8 Hz,2H), 3.85 (dd, J=10 Hz and J=5 Hz, 1H), 3.98 (dd, J=10 Hz and J=4 Hz,1H), 4.31 (dd, J=12 Hz and J=7 Hz, 1H), 4.33-4.38 (m, 1H), 4.40 (dd,J=12 Hz and J=5 Hz), 6.42 (dd, J=3 Hz and J=1 Hz, 1H), 6.81 (d, J=9 Hz,2H), 7.03 (dd, J=8 Hz and J=1 Hz, 1H), 7.08 (d, J=9 Hz, 2H), 7.09 (d,J=3 Hz, 1H), 7.29 (d, J=8 Hz, 1H), 7.41 (m, 1H)

B. 1-(5-Methylindole-1-yl)-3-(4-octylphenoxy)propan-2-one

The preparation is based on1-(5-methylindole-1-yl)-3-(4-octylphenoxy)propan-2-ol in analogy to thesynthesis of step C of Example 9. Deviating therefrom, the reaction timeis 19 h. The chromatographic purification on silica gel is carried outwith the flow agent petroleum ether/ethyl acetate 97:3. The productaccrues as a solid.

M.: 75° C.

C₂₆H₃₃NO₂ (391.6)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.27-1.31 (m, 10H),1.55-1.59 (m, 2H), 2.44 (s, 3H), 2.56 (t, J=8 Hz, 2H), 4.57 (s, 2H),5.12 (s, 2H), 6.51 (d, J=3 Hz, 1H), 6.79 (d, J=9 Hz, 2H), 7.00-7.02 (m,3H), 7.11 (d, J=9 Hz, 2H), 7.42-7.43 (m, 1H)

EXAMPLE 13 1-(5-Chloroindol-1-yl)-3-(4-octylphenoxy)propan-2-one A.1-(5-Chloroindol-1-yl)-3-(4-octylphenoxy)propan-2-ol

The preparation is based on 5-chloroindole in analogy to the synthesisof step B of Example 9. Deviating therefrom, the reaction is carried outat room temperature. The reaction time is 17 h. The chromatographicpurification on silica gel is carried out with the flow agent petroleumether/ethyl acetate 95:5. The product accrues as an oil.

C₂₅H₃₂ClNO₂ (414.0)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.26-1.31 (m, 10H),1.55-1.59 (m, 2H), 2.36 (s, broad, 1H), 2.55 (t, J=8 Hz, 2H), 3.83 (dd,J=10 Hz and J=5 Hz, 1H), 3.92 (dd, J=10 Hz and J=4 Hz, 1H), 4.27-4.42(m, 3H), 6.45 (dd, J=3 Hz and J=1 Hz, 1H), 6.80 (d, J=9 Hz, 2H), 7.09(d, J=9 Hz, 2H), 7.13 (dd, J=9 Hz and J=2 Hz, 1H), 7.16 (d, J=3 Hz, 1H),7.30 (d, J=9 Hz, 1H), 7.58 (d, J=2 Hz, 1H)

B. 1-(5-Chloroindol-1-yl)-3-(4-octylphenoxy)propan-2-one

The preparation is based on1-(5-chloroindol-1-yl)-3-(4-octylphenoxy)propan-2-ol in analogy to thesynthesis of step C of Example 9. Deviating therefrom, the reaction timeis 16 h. The product accrues as a solid and is recrystallized frompetroleum ether.

Mp.: 77° C.

C₂₅H₃₀ClNO₂ (412.0)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.28-1.32 (m, 10H),1.56-1.60 (m, 2H), 2.57 (t, J=8 Hz, 2H), 4.61 (s, 2H), 5.17 (s, 2H),6.52 (dd, J=3 Hz and J=1 Hz, 1H), 6.82 (d, J=9 Hz, 2H), 6.99 (d, J=9 Hz,1H), 7.05 (d, J=3 Hz, 1H), 7.12-7.15 (m, 3H), 7.60 (d, J=2 Hz, 1H)

EXAMPLE 14 1-(5-Methoxyindol-1-yl)-3-(4-octylphenoxy)propan-2-one A.1-(5-Methoxyindol-1-yl)-3-(4-octylphenoxy)propan-2-ol

The preparation is based on 5-methoxyindole in analogy to the synthesisof step B of Example 9. Deviating therefrom, the reaction is carried outat room temperature and in the absence of light. The reaction time is 17h. The chromatographic purification is carried out on silica gel (flowagent: petroleum ether/ethyl acetate 93:7). The product accrues as anoil.

C₂₆H₃₅NO₃ (409.6)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.27-1.31 (m, 10H),1.55-1.59 (m, 2H), 2.35 (d, J=5 Hz, 1H), 2.55 (t, J=8 Hz, 2H), 3.84 (dd,J=10 Hz and J=5 Hz, 1H), 3.85 (s, 3H), 3.91 (dd, J=10 Hz and J=4 Hz,1H), 4.27-4.40 (m, 3H), 6.43 (dd, J=3 Hz and J=1 Hz, 1H), 6.80 (d, J=9Hz, 2H), 6.86 (dd, J=9 Hz and J=3 Hz, 1H), 7.08 (d, J=9 Hz, 2H), 7.09(d, J=3 Hz, 1H), 7.11 (d, J=3 Hz, 1H), 7.28 (d, J=9 Hz, 1H)

B. 1-(5-Methoxyindol-1-yl)-3-(4-octylphenoxy)propan-2-one

The preparation is based on1-(5-methoxyindol-1-yl)-3-(4-octylphenoxy)propan-2-ol in analogy to thesynthesis of step C of Example 9. Deviating therefrom, the reaction timeis 18 h. The reaction is carried in the absence of light. The productaccrues as a solid.

Mp.: 85° C.

C₂₆H₃₃NO₃ (407.6)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.27-1.31 (m, 10H),1.55-1.57 (m, 2H), 2.56 (t, J=8 Hz, 2H), 3.85 (s, 3H), 4.56 (s, 2H),5.12 (s, 2H), 6.51 (dd, J=3 Hz and J=1 Hz, 1H), 6.80 (d, J=9 Hz, 2H),6.86 (dd, J=9 Hz and J=2 Hz, 1H), 7.01 (d, J=9 Hz, 1H), 7.02 (d, J=3 Hz,1H), 7.10 (d, J=2 Hz, 1H), 7.12 (d, J=9 Hz, 2H)

EXAMPLE 15 1-(3-(4-Octylphenoxy)-2-oxopropyl]indole-5-carbonitrile A.1-[2-Hydroxy-3-(4-octylphenoxy)propyl]indole-5-carbonitrile

The preparation is based on indole-5-carbonitrile in analogy of thesynthesis of step B of Example 9. Deviating therefrom, the reaction timeis 5 h. The chromatographic purification is initially carried out onsilica gel (flow agent: dichloromethane) and then on RP18 material (flowagent acetonitrile/water 75:25). The product accrues as an oil.

C₂₆H₃₂N₂O₂ (404.5)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.28-1.32 (m, 10H),1.55-1.61 (m, 2H), 2.47 (s, broad, 1H), 2.56 (t, J=8 Hz, 2H), 3.85 (dd,J=9 Hz and J=5 Hz, 1H), 3.95 (dd, J=9 Hz and J=4 Hz, 1H), 4.33-4.39 (m,2H), 4.47 (dd, J=17 Hz and J=7 Hz, 1H), 6.60 (dd, J=3 Hz and J=1 Hz,1H), 6.83 (d, J=9 Hz, 2H), 7.11 (d, J=9 Hz, 2H), 7.29 (d, J=3 Hz, 1H),7.41 (dd, J=9 Hz and J=2 Hz, 1H), 7.46 (d, J=9 Hz, 1H), 7.97 (s, 1H)

B. 1-(3-(4-Octylphenoxy)-2-oxopropyl]indole-5-carbonitrile

The preparation is based on1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carbonitrile in analogyto the synthesis of step C of Example 9. Deviating therefrom, thereaction time is 15 h. The chromatographic purification on silica gel iscarried out with the flow agent petroleum ether/ethyl acetate 90:10. Theproduct accrues as a solid and is recrystallized from petroleumether/ethyl acetate 95:5.

Mp.: 96° C.

C₂₆H₃₀N₂O₂ (402.5)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.28-1.32 (m, 10H),1.58-1.62 (m, 2H), 2.59 (t, J=8 Hz, 2H), 4.67 (s, 2H), 5.27 (s, 2H),6.67 (dd, J=3 Hz and J=1 Hz, 1H), 6.85 (d, J=9 Hz, 2H), 7.11 (d, J=9 Hz,1H), 7.14 (d, J=3 Hz, 1H), 7.16 (d, J=9 Hz, 2H), 7.41 (dd, J=9 Hz andJ=2 Hz, 1H), 7.99 (dd, J=2 Hz and J=1 Hz, 1H)

EXAMPLE 16 1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-5-carbaldehyde A.1-[2-Hydroxy-3-(4-octylphenoxy)propyl]indole-5-carbaldehyde

The preparation is based on indole-5-carbaldehyde in analogy to thesynthesis of step B of Example 9. The chromatographic purification isinitially carried out on silica gel (flow agent: dichloromethane) andthen on RP18 material (flow agent: acetonitrile/water 4:1). The productaccrues as a solid.

M.: 79° C.

C₂₆H₃₃NO₃ (407.6)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.26-1.30 (m, 10H),1.55-1.59 (m, 2H), 2.44 (s, broad, 1H), 2.55 (t, J=8 Hz, 2H), 3.86 (dd,J=10 Hz and J=5 Hz, 1H), 3.96 (dd, J=10 Hz and J=4 Hz, 1H), 4.34-4.40(m, 2H), 4.48 (dd, J=17 Hz and J=7 Hz, 1H), 6.68 (dd, J=3 Hz and J=1 Hz,1H), 6.80 (d, J=9 Hz, 2H), 7.09 (d, J=9 Hz, 2H), 7.26 (d, J=3 Hz, 1H),7.48 (d, J=9 Hz, 1H), 7.76 (dd, J=9 Hz and J=2 Hz, 1H), 8.14 (d, J=1 Hz,1H), 10.00 (s, 1H)

B. 1-(3-(4-Octylphenoxy)-2-oxopropyl]indole-5-carbaldehyde

The preparation is based on1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carbaldehyde in analogyto the synthesis of step C of Example 9. Deviating therefrom, thereaction time is 16 h. The chromatographic purification on silica gel iscarried out with the flow agent petroleum ether/ethyl acetate 9:1. Theproduct accrues as a solid.

Mp.: 96° C.

C₂₆H₃₁NO₃ (405.5)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.28-1.32 (m, 10H),1.59-1.63 (m, 2H), 2.58 (t, J=8 Hz, 2H), 4.67 (s, 2H), 5.26 (s, 2H),6.74 (dd, J=3 Hz and J=1 Hz, 1H), 6.85 (d, J=9 Hz, 2H), 7.12 (d, J=3 Hz,1H), 7.15 (d, J=9 Hz, 2H), 7.16 (d, J=9 Hz, 1H), 7.76 (dd, J=9 Hz andJ=1 Hz, 1H), 8.16-8.17 (m, 1H), 10.02 (s, 1H)

EXAMPLE 17 Methyl-1-(3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylateA. Methyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylate

The preparation is based on methylindole-5-carboxylate in analogy to thesynthesis of step B of Example 9. Deviating therefrom, the reaction timeis 6 h. The product accrues as a solid.

Mp.: 58° C.

C₂₇H₃₅NO₄ (437.6)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.27-1.30 (m, 10H),1.55-1.59 (m, 2H), 2.41 (s, broad, 1H), 2.55 (t, J=8 Hz, 2H), 3.85 (dd,J=10 Hz and J=5 Hz, 1H), 3.93 (s, 3H), 3.95 (dd, J=10 Hz and J=5 Hz,1H), 4.33-4.39 (m, 2H), 4.43-4.49 (m, 1H), 6.61 (dd, J=3 Hz and J=1 Hz,1H), 6.80 (d, J=9 Hz, 2H), 7.09 (d, J=9 Hz, 2H), 7.22 (d, J=3 Hz, 1H),7.40 (d, J=9 Hz, 1H), 7.90 (dd, J=9 Hz and J=2 Hz, 1H), 8.39 (m, 1H)

B. Methyl-1-(3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylate

The preparation is based onmethyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylate inanalogy to the synthesis of step C of Example 9. Deviating therefrom,the reaction time is 19 h. The product accrues as a solid and isrecrystallized (without chromatographic purification) from petroleumether/ethyl acetate 94:6.

Mp.: 118° C.

C₂₇H₃₃NO₄ (435.6)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.27-1.31 (m, 10H),1.57-1.60 (m, 2H), 2.57 (t, J=8 Hz, 2H), 3.92 (s, 3H), 4.63 (s, 2H),5.22 (s, 2H), 6.67 (dd, J=3 Hz and J=1 Hz, 1H), 6.83 (d, J=9 Hz, 2H),7.08-7.10 (m, 2H), 7.14 (d, J=9 Hz, 2H), 7.89 (dd, J=9 Hz and J=2 Hz,1H), 8.39 (m, 1H)

EXAMPLE 183-tert-Butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid

The compound accrues in the synthesis of1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (Example 10)as a by-product and can be separated therefrom in the purification bymeans of RP-HPLC.

Mp.: 146-147° C.

C₃₀H₃₉NO₄ (477.6)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=6 Hz, 3H), 1.26-1.30 (m, 10H), 1.46(s, 9H), 1.56-1-60 (m, 2H), 2.57 (t, J=8 Hz, 2H), 4.62 (s, 2H), 5.15 (s,2H), 6.82 (m, 3H), 7.09 (d, J=9 Hz, 1H), 7.14 (d, J=9 Hz, 2H), 7.93 (dd,J=8 Hz and J=1 Hz, 1H), 8.65 (s, 1H).

EXAMPLE 193-Chloro-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid A.tert-Butyl-3-chloroindole-5-carboxylate

A solution of 389 mg (1.79 mmol) tert-butylindole-5-carboxylate in 12 mlmethanol is mixed with 335 mg (2.50 mmol) N-chlorosuccinimide andstirred at room temperature overnight. The methanol is removed byrotation and the resulting residue is taken up in 15 ml ethyl acetate.The organic phase is washed twice with 1M sodium hydrogen carbonatesolution, dried on sodium sulfate and concentrated by rotation. Columnchromatographic processing of the residue on silica gel (flow agent:hexane/ethyl acetate 9:1) yields a solid.

Yield: 190 mg (0.76 mmol); 42%).

C₁₃H₁₄ClNO₂ (251.1)

Mp.: 120° C.

¹H-NMR (CDCl₃): δ (ppm)=1.64 (s, 9H), 7.22 (d, J=1 Hz, 1H), 7.35 (d, J=9Hz, 1H), 7.90 (d, J=9 Hz, 1H), 8.33 (d, J=1 Hz, 1H), 8.39 (s, 1H)

B.tert-Butyl-3-chloro-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylate

The preparation is based on tert-butyl-3-chloroindole-4-carboxylate inanalogy to the synthesis of step B of Example 9. Deviating therefrom,the reaction time is 8 h. The chromatographic purification on silica gelis carried out with dichloromethane as flow agent. The product accruesas an oil.

C₃₀H₄₀ClNO₄ (514.1)

¹H-NMR (CDCl₃): δ (ppm)=0.86 (t, J=7 Hz, 3H), 1.28 (m, 10H), 1.59 (m,2H), 1.63 (s, 9H), 2.53 (s, broad, 1H), 2.56 (t, J=8 Hz, 2H), 3.83 (dd,J=10 Hz and J=5 Hz, 1H), 3.93 (m, 1H), 4.28-4.40 (m, 2H), 4.28-4.40 (m,3H), 6.79 (d, J=9 Hz, 2H), 7.09 (d, J=9 Hz, 2H), 7.21 (s, 1H), 7.36 (d,J=9 Hz, 1H), 7.88 (dd, J=9 Hz and J=2 Hz, 1H), 8.30 (d, J=2 Hz, 1H)

C.tert-Butyl-3-chloro-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylate

The preparation is based ontert-butyl-3-chloro-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylatein analogy to the synthesis of step C of Example 9. The chromatographicpurification on silica gel is carried out by means of the flow agentpetroleum ether/ethyl acetate 9:1. The product accrues as an oil.

C₃₀H₃₈ClNO₄ (512.1)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.26 (m, 10H), 1.59 (m,2H), 1.64 (s, 9H), 2.58 (t, J=8 Hz, 2H), 4.66 (s, 2H), 5.18 (s, 2H),6.84 (d, J=8 Hz, 2H), 7.06 (m, 2H), 7.16 (d, J=8 Hz, 2H), 7.94 (d, J=9Hz, 1H), 8.31 (s, 1H)

D. 3-Chloro-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid

The preparation is based ontert-butyl-3-chloro-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylatein analogy to the synthesis of step D of Example 9. The product accruesas a solid and is recrystallized (without chromatographic purification)from hexane/tetrahydrofurane.

Mp.: 157° C.

C₂₆H₃₀ClNO₄ (456.0)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=6 Hz, 3H), 1.28 (m, 10H), 1.62 (m,2H), 2.58 (t, J=8 Hz, 2H), 4.68 (s, 2H), 5.22 (s, 2H), 6.91 (d, J=8 Hz,2H), 7.09 (m, 2H), 7.16 (d, J=8 Hz, 2H), 7.97 (d, J=9 Hz, 1H), 8.47 (s,1H)

EXAMPLE 203-Formyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid A.tert-Butyl-3-formylindole-5-carboxylate

0.4 ml (4.87 mmol) oxalylchloride are dissolved in a three-neck flaskunder nitrogen in 15 ml absolute dichloromethane and cooled to 0° C.Thereafter, 0.4 ml absolute dimethylformamide dissolved in 15 mlabsolute dichloromethane is added. The mixture is stirred on ice coolingfor 20 minutes, gas generation and the formation of a colorlessprecipitate being observed. Then, 1.00 g (4.64 mmol)tert-butylindole-5-carboxylate is added and the reaction mixture isallowed to heat to room temperature. Stirring is continued for another20 min, the suspension is transferred using tetrahydrofurane to a roundflask and concentrated on a rotary evaporator. The residue is taken upin 40 ml tetrahydrofurane, mixed with 50 ml 20% sodium acetate solutionand heated under reflux for 30 minutes. After cooling down, 30 ml 5%sodium hydrogen carbonate solution are added, extracted three timesusing ethyl acetate, the volume of the combined organic phases isconcentrated to about 150 ml and washed with saturated NaCl solution.The organic phase is dried on sodium sulfate and the solvent is removedon the rotary evaporator. Recrystallization of the crude product fromn-hexane/ethyl acetate supplies the product as a solid.

Yield: 0.81 g (3.30 mmol); 71%

C₁₄H₁₅NO₃ (245.3)

Mp.: 190° C.

¹H-NMR (DMSO-d₆): δ (ppm)=1.55 (s, 9H), 7.56 (dd, J=9 Hz and J=1 Hz,1H), 7.81 (dd, J=9 Hz and J=2 Hz, 1H), 8.39 (d, J=3 Hz, 1H), 8.67 (d,J=2 Hz, 1H), 9.94 (s, broad, 1H), 12.40 (s, broad, 1H)

B.tert-Butyl-3-formyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylate

The preparation is based on tert-butyl-3-formylindole-5-carboxylate inanalogy to the synthesis of step B of Example 9. Deviating therefrom,the reaction batch is heated to 120° C. for 12 hours. Thechromatographic purification on silica gel is carried out usingpetroleum ether/ethyl acetate 3:2 as flow agent. The product accrues asan oil.

C₃₁H₄₁NO₅ (507.7)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.27 (m, 10H), 1.59 (m,2H), 1.63 (s, 9H), 2.55 (t, J=8 Hz, 2H), 3.07 (s, broad, 1H), 3.98 (m,2H), 4.37 (dd, J=14 Hz and J=7 Hz, 1H), 4.51 (m, 1H), 4.54 (dd, J=14 Hzand J=4 Hz, 1H), 6.82 (d, J=9 Hz, 2H), 7.10 (d, J=9 Hz, 2H), 7.41 (d,J=9 Hz, 1H), 7.86 (s, 1H), 7.94 (d, J=9 Hz, 1H), 8.81 (s, 1H), 9.86 (s,1H)

C.tert-Butyl-3-formyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylate

The preparation is based ontert-butyl-3-formyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylatein analogy to the synthesis of step C of Example 9. Deviating therefrom,the reaction time is 20 h. The chromatographic purification on silicagel is carried out using the flow agent petroleum ether/ethyl acetate3:2. The product accrues as an oil.

C₃₁H₃₉NO₅ (505.3)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.29 (m, 10H), 1.63 (m,11H), 2.58 (t, J=8 Hz, 2H), 4.71 (s, 2H), 5.33 (s, 2H), 6.87 (d, J=8 Hz,2H), 7.08 (d, J=9 Hz, 1H), 7.17 (d, J=8 Hz, 2H), 7.72 (s, 1H), 7.95 (d,J=9 Hz, 1H), 8.92 (s, 1H), 10.05 (s, 1H)

D. 3-Formyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid

The preparation is based ontert-butyl-3-formyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylatein analogy to the synthesis of step D of Example 9. Deviating therefrom,the reaction time is only 3 h. The chromatographic purification by meansof RP-HPLC is carried out with the flow agent acetonitrile/water 9:1.The product accrues as a solid

Mp.: 193° C.

C₂₇H₃₁NO₅ (449.5)

¹H-NMR (DMSO-d₆): δ (ppm)=0.83 (t, J=7 Hz, 3H), 1.24 (m, 10H), 1.51 (m,2H), 2.51 (t, J=8 Hz, 2H), 5.03 (s, 2H), 5.58 (s, 2H), 6.90 (d, J=9 Hz,2H), 7.11 (d, J=9 Hz, 2H), 7.60 (d, J=9 Hz, 1H), 7.86 (dd, J=9 Hz andJ=2 Hz, 1H), 8.29 (s, 1H), 8.74 (d, J=2 Hz, 1H), 9.97 (s, 1H)

EXAMPLE 213-Acetyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid A.Methyl-3-acetylindole-5-carboxylate

In a three-neck flask, 4.20 ml (9.25 mmol) of a 2.2 M ZnCl₂ solution in20 ml absolute dichloromethane is charged under nitrogen and thesolution is cooled to 0° C. using an ice bath. Thereafter, 5.62 ml (8.99mmol) of a 1.6 M n-butyllithium solution are slowly added drop-wise. Thereaction mixture is heated to room temperature, stirred for 1 hour, thenadmixed with the solution of 1.50 g (8.56 mmol)methylindole-5-carboxylate in 20 ml absolute dichloromethane and stirredagain at room temperature for one hour. Thereafter, the batch is cooledto 0° C. and 1.28 ml (18.1 mmol) acetylchloride is carefully added so asto form an orange suspension. The latter is stirred at room temperaturefor 1 hour. Then, 0.93 g (7.02 mmol) aluminum chloride is added. Afteranother hour of stirring at room temperature, hydrolysis withsemi-saturated NaCl solution is carried out and 100 ml ethyl acetate and20 ml tetrahydrofurane are added. Three extractions are carried outusing ethyl acetate, the combined organic phases are washed withsaturated NaCl solution and the organic phase is dried on sodiumsulfate. The solvent is distilled off. Chromatographic purification ofthe residue on silica gel (flow agent: hexane/ethyl acetate 3:2) yieldsthe product as a solid.

Yield: 0.70 g (3.23 mmol); 38%

Mp.: 235-236° C.

C₁₂H₁₁NO₃ (217.2)

¹H-NMR (DMSO-d₆): δ (ppm)=2.49 (s, 3H), 3.87 (s, 3H), 7.53 (dd, J=9 Hzand J=1 Hz, 1H), 7.82 (dd, J=9 Hz and J=2 Hz, 1H), 8.43 (d, J=3 Hz, 1H),8.85 (d, J=1 Hz, 1H), 12.23 (s, broad, 1H)

B. 3-Acetylindole-5-carboxylic acid

0.686 g (3.16 mmol) methyl-3-acetylindole-5-carboxylate are dissolvedunder heat in 10 ml tetrahydrofurane and 10 ml ethylene glycol and mixedwith 7.08 g (0.13 mol) potassium hydroxide. Having stirred under refluxfor 30 minutes, the reaction mixture is cooled to room temperature. Thetetrahydrofurane is removed on the rotary evaporator and the solution isacidified under ice cooling with 20 ml 6N hydrochloric acid. Theprecipitated light violet precipitate is sucked off and dried.

Yield: 0.64 g (3.16 mmol)

Mp.: 364° C.

C₁₁H₀₉NO₃ (203.2)

¹H-NMR (DMSO-d₆): δ (ppm)=2.47 (s, 3H), 7.50 (dd, J=9 Hz and J=1 Hz,1H), 7.86 (dd, J=9 Hz and J=2 Hz, 1H), 8.41 (d, 1H), 8.82 (d, 1H), 12.17(s, broad, 1H), 12.57 (s, broad, 1H)

C. tert-Butyl-3-acetylindole-5-carboxylate

The preparation is based on 3-acetylindole-5-carboxylic acid in analogyto the synthesis of step A of Example 9. The chromatographicpurification on silica gel is carried out with hexane/ethyl acetate 3:2as flow agent.

Mp.: 214° C.

C₁₅H₁₇NO₃ (259.1)

¹H-NMR (DMSO-d₆): δ (ppm)=1.56 (s, 9H), 2.46 (s, 3H), 7.50 (d, J=8 Hz,1H), 7.76 (d, J=8 Hz, 1H), 8.40 (s, 1H), 8.78 (s, 1H), 12.17 (s, broad,1H)

D.tert-Butyl-3-acetyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylate

The preparation is based on tert-butyl-3-acetylindole-5-carboxylate inanalogy to the synthesis of step B of Example 9. Deviating therefrom,the reaction batch is heated at 120° C. for 26 h. The chromatographicpurification on silica gel is carried out using petroleum ether/ethylacetate 3:2 as flow agent. The product accrues as an oil.

C₃₂H₄₃NO₅ (521.7)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.28 (m, 10H), 1.57 (m,2H), 1.64 (s, 9H), 2.31 (s, 3H), 2.34 (s, broad, 1H), 2.55 (t, J=8 Hz,2H), 3.99 (m, 2H), 4.32 (dd, J=14 Hz and J=7 Hz, 1H), 4.50 (m, 1H), 4.53(dd, J=12 Hz and J=4 Hz, 1H), 6.75 (d, J=9 Hz, 2H), 7.10 (d, J=9 Hz,2H), 7.38 (d, J=9 Hz, 1H), 7.83 (s, 1H), 7.88 (dd, J=7 Hz and J=3 Hz,1H), 8.84 (d, J=3 Hz, 1H)

E.tert-Butyl-3-acetyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylate

The preparation is based ontert-butyl-3-acetyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carboxylatein analogy to the synthesis of step C of Example 9. The chromatographicpurification on silica gel is carried out using the flow agent petroleumether/ethyl acetate 17:3. The product accrues as an oil.

C₃₂H₄₁NO₅ (519.3)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.30 (m, 10H), 1.58 (m,2H), 1.62 (s, 9H), 2.53 (s, 3H), 2.59 (t, J=8 Hz, 2H), 4.69 (s, 2H),5.29 (s, 2H), 6.86 (d, J=7 Hz, 2H), 7.07 (d, J=9 Hz, 1H), 7.17 (d, J=7Hz, 2H), 7.71 (s, 1H), 7.92 (dd, J=9 Hz and J=2 Hz, 1H), 9.00 (d, J=2Hz, 1H)

F. 3-Acetyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid

The preparation is based ontert-butyl-3-acetyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylatein analogy to the synthesis of step D of Example 9. The product accruesas a solid and is recrystallized (without chromatographic purification)from hexane/tetrahydrofurane.

Mp.: 197° C.

C₂₈H₃₃NO₅ (463.6)

¹H-NMR (DMSO-d₆): δ (ppm)=0.83 (t, J=7 Hz, 3H), 1.23 (m, 10H), 1.51 (m,2H), 2.47 (m, 2H), 2.51 (s, 3H), 5.03 (s, 2H), 5.53 (s, 2H), 6.89 (d,J=8 Hz, 2H), 7.10 (d, J=8 Hz, 2H), 7.56 (d, J=9 Hz, 1H), 7.81 (dd, J=9Hz and J=1 Hz, 1H), 8.33 (s, 1H), 8.83 (d, J=1 Hz, 1H)

EXAMPLE 223-Methoxycarbonyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylicacid A. 5-tert-Butyl-3-methylindole-3,5-dicarboxylate

0.70 g (14.3 mmol) sodium cyanide is added to a solution of 0.70 g (2.83mmol) tert-butyl-3-formylindole-5-carboxylate in 30 ml methanol. Ayellow solution forms which is admixed spatula-wise with 4.92 g (57.2mmol) activated brownstone. Stirring is carried out at room temperaturefor 48 hours. Having added 80 ml dichloromethane and 5 g Celite, theblack suspension is sucked off on a suction filter, the residue iswashed with dichloromethane and the filtrate is extracted by shaking forcomplexing excess cyanide ions with a freshly prepared iron (II) sulfatesolution. The organic phase is washed with saturated NaCl solution,dried on sodium sulfate and concentrated. The product is obtained as asolid.

Yield: 0.743 g (2.69 mmol); 94%

Mp: 196° C.

C₁₅H₁₇NO₄ (275.3)

¹H-NMR (CDCl₃): δ (ppm)=1.58 (s, 9H), 3.94 (s, 3H), 7.42 (d, J=9 Hz,1H), 7.92 (d, 1H), 7.99 (d, 1H), 8.84 (d, J=1 Hz, 1H), 9.36 (s, broad1H)

B.5-tert-Butyl-3-methyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-3,5-dicarboxylate

The preparation is based on5-tert-butyl-3-methylindole-3,5-dicarboxylate in analogy to thesynthesis of step B of Example 9. Deviating therefrom, the reactionbatch is heated at 120° C. for 14 h. The chromatographic purification onsilica gel is carried using petroleum ether/ethyl acetate 7:3 as flowagent. The product accrues as an oil.

C₃₂H₄₃NO₆ (537.7)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.28 (m, 10H), 1.57 (m,2H), 1.62 (s, 9H), 2.55 (t, J=8 Hz, 2H), 2.78 (s, broad, 1H), 3.90 (m,4H), 3.96 (dd, 1H), 4.37 (m, 2H), 4.47 (dd, J=10 Hz and J=4 Hz, 1H),6.80 (d, J=7 Hz, 2H), 7.10 (d, J=7 Hz, 2H), 7.40 (d, J=9 Hz, 1H), 7.91(dd, J=9 Hz and J=2 Hz, 1H), 7.96 (s, 1H), 8.79 (d, J=2 Hz, 1H)

C.5-tert-Butyl-3-methyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-3,5-dicarboxylate

The preparation is based on5-tert-butyl-3-methyl-1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-3,5-dicarboxylatein analogy to the synthesis of step C of Example 9. The chromatographicpurification on silica gel is carried out using the flow agenthexane/ethyl acetate 4:1. The product accrues as an oil.

C₃₂H₄₁NO₆ (535.7)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.29 (m, 10H), 1.59 (m,2H), 1.62 (s, 9H), 2.58 (t, J=7 Hz, 2H), 3.93 (s, 3H), 4.69 (s, 2H),5.27 (s, 2H), 6.85 (d, J=9 Hz, 2H), 7.06 (dd, J=9 Hz and J=1 Hz, 1H),7.16 (d, J=9 Hz, 2H), 7.72 (s, 1H), 7.90 (dd, J=9 Hz and J=2 Hz, 1H),8.83 (dd, J=2 Hz and J=1 Hz, 1H)

D.3-Methoxycarbonyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylicacid

The preparation is based on5-tert-butyl-3-methyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-3,5-dicarboxylatein analogy to the synthesis of step D of Example 9. Deviating therefrom,the reaction time is only 2 h. The product accrues as a solid and isrecrystallized (without chromatographic purification) fromhexane/tetrahydrofurane.

Mp.: 208° C.

C₂₈H₃₃NO₆ (479.6)

¹H-NMR (DMSO-d₆): δ (ppm)=0.83 (t, J=7 Hz, 3H), 1.22 (m, 10H), 1.50 (m,2H), 2.53 (m, 2H), 3.83 (s, 3H), 5.00 (s, 2H), 5.52 (s, 2H), 6.88 (d,J=9 Hz, 2H), 7.09 (d, J=9 Hz, 2H), 7.57 (d, J=9 Hz, 1H), 7.80 (dd, J=9Hz and J=2 Hz, 1H), 8.16 (s, 1H), 8.65 (d, J=1 Hz, 1H)

EXAMPLE 233-tert-Butyl-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-6-carboxylic acid

The compound accrues in the synthesis of1-[3-(4-octylphenoxy)-2-oxopropyl]indole-6-carboxylic acid (Example 11)as a by-product and can be separated therefrom by purification usingRP-HPLC.

Mp.: 145-146° C.

C₃₀H₃₉NO₄ (477.6)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=6 Hz, 3H), 1.27-1.30 (m, 10H), 1.46(s, 9H), 1.58-1.62 (m, 2H), 2.59 (t, J=8 Hz, 2H), 4.64 (s, 2H), 5.23 (s,2H), 6.86 (d, J=9 Hz, 2H), 6.96 (s, 1H), 7.16 (d, J=9 Hz, 2H), 7.87 (m,2H), 7.96 (m, 1H)

EXAMPLE 24 1-[3-(4-Decyloxyphenoxy)-2-oxopropyl]indole-5-carboxylic acidA.tert-Butyl-1-[3-(4-decyloxyphenoxy)-2-hydroxypropyl]indole-5-carboxylate

The preparation is based on tert-butylindole-5-carboxylate and2-(4-decyloxyphenoxymethyl)oxirane in analogy to the synthesis of step Bof Example 9. Deviating therefrom, the reaction time is 5 h. Thechromatographic purification is initially carried out on silica gel(flow agent: petroleum ether/ethyl acetate 85:15) and then on RP18material (flow agent acetonitrile/water 4:1). The product accrues as anoil.

C₃₂H₄₅NO₅ (523.7)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.27-1.34 (m, 12H),1.42-1.46 (m, 2H), 1.62 (s, 9H), 1.75 (quin, J=7 Hz, 2H), 2.45 (s,broad, 1H), 3.79 (dd, J=10 Hz and J=5 Hz, 1H), 3.88-3.91 (m, 3H),4.32-4.36 (m, 2H), 4.43 (dd, J=16 Hz and J=8 Hz, 1H), 6.59 (dd, J=3 Hzand J=1 Hz, 1H), 6.78-6.85 (m, 4H), 7.19 (d, J=3 Hz, 1H), 7.36 (d, J=9Hz, 1H), 7.85 (dd, J=9 Hz and J=2 Hz, 1H), 8.32 (m, 1H)

B. tert-Butyl-1-[3-(4-decyloxyphenoxy)-2-oxopropyl]indole-5-carboxylate

The preparation is based ontert-butyl-1-[3-(4-decyloxyphenoxy)-2-hydroxypropyl]indole-5-carboxylatein analogy to the synthesis of step C of Example 9. The chromatographicpurification on silica gel is carried out using the flow agent petroleumether/ethyl acetate 9:1. The product accrues as a solid.

C₃₂H₄₃NO₅ (521.7)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.27-1.34 (m, 12H),1.41-1.45 (m, 2H), 1.62 (s, 9H), 1.77 (quin, J=7 Hz, 2H), 3.91 (t, J=7Hz, 2H), 4.59 (s, 2H), 5.21 (s, 2H), 6.67 (d, J=3 Hz, 1H), 6.82-6.87 (m,4H), 7.08 (d, J=3 Hz, 1H), 7.09 (d, J=9 Hz, 1H), 7.86 (dd, J=9 Hz andJ=2 Hz, 1H), 8.34 (d, J=1 Hz, 1H)

C. 1-[3-(4-Decyloxyphenoxy)-2-oxopropyl]indole-5-carboxylic acid

50 mg (0.096 mmol)tert-butyl-1-[3-(4-decyloxyphenoxy)-2-oxopropyl]indole-5-carboxylate aredissolved in 15 ml absolute dichloromethane and mixed with 0.82 g (7.19mmol) trifluoroacetic acid. Having stirred at room temperature for 4hours, the batch is concentrated to dryness on the rotary evaporator.Three admixtures with 10 ml of a mixture of petroleum ether and ethylacetate (4:1) each and respective concentration to dryness on the rotaryevaporator leave as a crude product a solid which is purified on anRP-HPLC column by means of chromatography (stationary phase: cromasil,flow agent: acetonitrile/water 90:10).

Yield: 25 mg (0.05 mmol); 56%

Mp.: 137° C.

C₂₈H₃₅NO₅ (465.6)

¹H-NMR (CDCl₃): δ (ppm)=0.89 (t, J=7 Hz, 3H), 1.28-1.33 (m, 12H),1.43-1.49 (m, 2H), 1.75-1.82 (m, 2H), 3.93 (t, J=7 Hz, 2H), 4.63 (s,2H), 5.25 (s, 2H), 6.72 (dd, J=3 Hz and J=1 Hz, 1H), 6.84-6.89 (m, 4H),7.12 (d, J=3 Hz, 1H), 7.14 (d, J=9 Hz, 1H), 7.97 (dd, J=9 Hz and J=2 Hz,1H), 8.50 (d, J=1 Hz, 1H)

EXAMPLE 25 1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-5-carbamide A.1-[2-Hydroxy-3-(4-octylphenoxy)propyl]indole-5-carbamide

0.18 g (0.44 mmol)1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carbonitrile (Example15A) is dissolved in 15 ml tert-butanol, mixed with 0.23 g (3.6 mmol)pulverized, 88% potassium hydroxide and heated under reflux for 11 h.Having cooled down, the mixture is hydrolyzed in water and acidifiedwith 1N hydrochloric acid. Three extractions with diethyl ether,concentration to half the volume on the rotary evaporator, washing withwater and with saturated NaCl solution, drying on sodium sulfate,filtration and reconcentration on the rotary evaporator leave as a crudeproduct a yellowish solid which is purified on silica gel by means ofcolumn chromatography (flow agent: petroleum ether/ethyl acetate 1:1)and yields the product as a solid.

Yield: 0.13 g (0.31 mmol); 70%

Mp.: 118-119° C.

C₂₆H₃₄N₂O₃ (422.6)

¹H-NMR (CDCl₃): δ (ppm)=0.88 (t, J=7 Hz, 3H), 1.26-1.30 (m, 10H),1.55-1.58 (m, 2H), 2.52 (m, 2H), 3.85 (dd, J=10 Hz and J=5 Hz, 1H), 3.94(dd, J=10 Hz and J=4 Hz, 1H), 4.32-4.39 (m, 2H), 4.46 (dd, J=17 Hz andJ=8 Hz, 1H), 5.40-6.28 (s, broad, 2H), 6.59 (d, J=3 Hz, 1H), 6.80 (d,J=9 Hz, 2H), 7.09 (d, J=9 Hz, 2H), 7.23 (d, J=3 Hz, 1H), 7.42 (d, J=9Hz, 1H), 7.66 (d, J=9 Hz, 1H), 8.12 (s, 1H)

B. 1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-5-carbamide

The preparation is based on1-[2-hydroxy-3-(4-octylphenoxy)propyl]indole-5-carbamide in analogy tothe synthesis of step C of Example 9. Deviating therefrom, the reactiontime is 19 h. The chromatographic purification on silica gel is carriedout using the flow agent petroleum ether/ethyl acetate 1:1. The productaccrues as a solid.

M.: 162-163° C.

C₂₆H₃₂N₂O₃ (420.5)

¹H-NMR (DMSO-d₆): δ (ppm)=0.84 (t, J=7 Hz, 3H), 1.23-1.26 (m, 10H),1.49-1.53 (m, 2H), 2.47-2.51 (m, 2H), 4.97 (s, 2H), 5.39 (s, 2H), 6.54(d, J=3 Hz, 1H), 6.85 (d, J=9 Hz, 2H), 7.07-7.10 (m, 3H), 7.33 (d, J=3Hz, 1H), 7.38 (d, J=9 Hz, 1H), 7.65 (d, J=9 Hz, 1H), 7.83 (s, broad,1H), 8.13 (s, 1H)

EXAMPLE 26 1-[3-(4-Heptyloxyphenoxy)-2-oxopropyl]indole-5-carbamide

A. 1-Oxiranylmethylindole-5-carbonitrile

2.07 g (42 mmol) pulverized, 88% potassium hydroxide, 3.0 g (0.021 mol)indole-5-carbonitrile and 0.68 g (2 mmol) tetrabutylammoniumbromide arejointly weighed out in the given order and mixed with 9.9 ml (126 mmol)epichlorohydrine with stirring. Stirring is continued overnight.Following hydrolysis and three extractions using ethyl acetate, thecombined organic phases are washed three times with water. Drying of theorganic phase using sodium sulfate and concentration of the solvent onthe rotary evaporator leaves a solid which is purified on silica gel bycolumn chromatography (flow agent: hexane/ethyl acetate 7:3).

Yield: 3.34 g (17 mmol); 80%

Mp.: 92° C.

C₁₂H₁₀N₂O (198.2)

¹H-NMR (CDCl₃): δ (ppm)=2.29 (dd, J=5 Hz and J=3 Hz, 1H), 2.77 (m, 1H),3.22 (m, 1H), 4.08 (dd, J=15 Hz and J=6 Hz, 1H), 4.47 (dd, J=15 Hz andJ=3 Hz, 1H), 6.54 (d, J=3 Hz, 1H), 7.20 (d, J=3 Hz, 1H), 7.40 (m, 2H),7.92 (s, 1H)

B. 1-[3-(4-Heptyloxyphenoxy)-2-hydroxypropyl]indole-5-carbonitrile

0.13 g (2.47 mmol) sodium hydride as 60% dispersion in mineral oil issuspended in 10 ml absolute DMF under nitrogen, stirred at roomtemperature for 10 min and mixed with the solution of 0.5 g (2.39 mmol)4-heptyloxyphenol in 5 ml absolute DMF. Having stirred for 1 hour, asolution of 475 mg (2.39 mmol) 1-oxiranylmethylindole-5-carbonitrile in5 ml absolute DMF is added and stirring is continued at room temperatureovernight. Thereafter, the suspension is hydrolyzed with semi-saturatedNaCl solution and extracted three times with ethyl acetate. The extractsare washed with saturated NaCl solution, dried on sodium sulfate and thesolvent is distilled off. The residue is purified on silica gel by meansof column chromatography (flow agent: hexane/ethyl acetate 1:1), theproduct accruing as an oil.

Yield: 0.48 g (1.18 mmol); 49%

C₂₅H₃₀N₂O₃ (406.5)

MS (EI): m/z (%)=406 (100) M⁺, 309 (20), 308 (92), 199 (62), 181 (25),156 (36), 155 (60), 110 (69)

C. 1-[3-(4-Heptyloxyphenoxy)-2-hydroxypropyl]indole-5-carbamide

455 mg (1.12 mmol)1-[3-(4-Heptyloxyphenoxy)-2-hydroxypropyl]indole-5-carbonitrile aredissolved in 10 ml tert-butanol. Having added 1.10 g (22.4 mmol)pulverized, 88% potassium hydroxide, the batch is heated to 100° C. for3 hours. After cooling the reaction solution, hydrolysis using 50 mldistilled water and neutralization with 1 N hydrochloric acid arecarried out. The aqueous phase is extracted three times with ethylacetate and the combined organic phases are washed once with water andthen twice with saturated sodium chloride solution. Following drying onsodium sulfate, the solvent is removed on the rotary evaporator. Theresidue is purified on silica gel by means of column chromatography(flow agent: ethyl acetate), the product accruing as a solid.

Yield: 245 mg (0.58 mmol); 52%

Mp.: 114° C.

C₂₅H₃₂N₂O₄ (424.5)

MS (EI): m/z (%)=424 (67) M⁺, 328 (21), 327 (100), 174 (18), 173 (69)

D. 1-[3-(4-Heptyloxyphenoxy)-2-oxopropyl]indole-5-carbamide

The preparation is based on1-[3-(4-heptyloxyphenoxy)-2-hydroxypropyl]indole-5-carbamide in analogyto the synthesis of step C of Example 9. Deviating therefrom, thereaction time is 20 h. The product is extracted from the reaction batchby means of ethyl acetate. The chromatographic purification on silicagel is carried out with the flow agent ethyl acetate. Followingrecrystallization from hexane/ethyl acetate, the product accrues as asolid.

M.: 157° C.

C₂₅H₃₀N₂O₄ (422.5)

¹H-NMR (DMSO-d₆): δ (ppm)=0.82 (t, J=7 Hz, 3H), 1.20-1.36 (m, 6H),1.37-1.42 (m, 2H), 1.62 (quin, J=7 Hz, 2H), 3.87 (t, J=7 Hz, 2H), 4.93(s, 2H), 5.39 (s, 2H), 6.54 (d, J=3 Hz, 1H), 6.82-6.93 (m, 4H), 7.21 (s,1H), 7.37 (d, J=3 Hz, 1H), 7.41 (d, J=8 Hz, 1H), 7.66 (dd, J=8 Hz andJ=2 Hz, 1H), 7.82 (s, 1H), 8.19 (d, J=2 Hz, 1H)

EXAMPLE 27 1-[3-(Biphenyl-4-yloxy)-2-oxopropyl]indole-5-carbamide A.1-[3-(Biphenyl-4-yloxy)-2-hydroxypropyl]indole-5-carbonitrile

0.34 g (2.02 mmol) 4-phenyl phenol are dissolved in 5 ml absolute THFunder nitrogen and mixed drop-wise with 0.1 ml (1.0 mmol)tert-butyllithium with constant stirring. The mixture is stirred at roomtemperature for 5 min. Thereafter, the solution of 0.20 g (1.0 mmol)1-oxiranylmethylindole-5-carbonitrile (Example 26A) in 5 ml absolute THFis added drop-wise. The batch is heated at 100° C. for 4 hours. Havingcooled down, the batch is mixed with 100 ml diethyl ether and extractedthree times using water. The aqueous phase is extracted twice usingethyl acetate and the combined organic phases are dried on sodiumsulfate, filtrated and the solvent is removed in vacuo. The residue ispurified on silica gel by means of column chromatography (flow agent:hexane/ethyl acetate 7:3). The product is obtained as a solid.

Yield: 0.37 g (1.0 mmol); 100%

Mp.: 133° C.

C₂₄H₂₀N₂O₂ (368.4)

¹H-NMR (DMSO-d₆): δ (ppm)=3.90-3.92 (m, 2H), 4.20 (m, 1H), 4.27 (dd,J=15 Hz and J=7 Hz, 1H), 4.42 (dd, J=15 Hz and J=4 Hz, 1H), 5.45 (d, J=5Hz, 1H), 6.60 (d, J=3 Hz, 1H), 7.04 (d, J=9 Hz, 2H), 7.30 (d, J=8 Hz,1H), 7.40 (d, J=8 Hz, 2H), 7.45 (d, J=8 Hz, 2H), 7.58 (d, J=3 Hz, 1H),7.59 (d, J=7 Hz, 1H), 7.62 (m, 2H), 7.72 (d, J=8 Hz, 1H), 8.35 (s, 1H)

B. 1-[3-(Biphenyl-4-yloxy)-2-hydroxypropyl]indole-5-carbamide

The preparation is based on1-[3-(biphenyl-4-yloxy)-2-hydroxypropyl]indole-5-carbonitrile in analogyto the synthesis of step C of Example 26. The product is obtained as asolid.

Mp.: 155° C.

C₂₄H₂₂N₂O₃ (386.4)

¹H-NMR (DMSO-d₆): δ (ppm)=3.88-3.92 (m, 2H), 4.19 (s, broad, 1H), 4.27(dd, J=14 Hz and J=7 Hz, 1H), 4.41 (dd, J=14 Hz and J=4 Hz, 1H), 5.48(s, broad, 1H), 6.51 (d, J=3 Hz, 1H), 7.02 (d, J=9 Hz, 2H), 7.10 (s,broad, 1H), 7.28-7.32 (m, 1H), 7.36-7.43 (m, 3H), 7.48-7.63 (m, 6H),7.83 (s, broad, 1H), 8.17 (s, 1H)

C. 1-[3-(Biphenyl-4-yloxy)-2-oxopropyl]indole-5-carbamide

The preparation is based on1-[3-(biphenyl-4-yloxy)-2-hydroxypropyl]indole-5-carbamide in analogy tothe synthesis of step D of Example 26. The product is obtained as asolid.

Mp.: 120° C.

C₂₄H₂₀N₂O₃ (384.4)

¹H-NMR (DMSO-d₆): δ (ppm)=5.09 (s, 2H), 5.21 (s, 2H), 6.57 (d, J=3 Hz,1H), 7.09 (d, J=9 Hz, 2H), 7.11 (s, broad, 1H), 7.28-7.33 (m, 1H), 7.35(d, J=3 Hz, 1H), 7.38-7.45 (m, 3H), 7.57-7.70 (m, 4H), 7.85 (s, broad,1H), 8.17 (s, 1H)

EXAMPLE 28 1-[3-(Biphenyl-3-yloxy)-2-oxopropyl]indole-5-carbamide A.1-[3-(Biphenyl-3-yloxy)-2-hydroxypropyl]indole-5-carbonitrile

The preparation is based on 3-phenyl phenol and1-oxiranylmethylindole-5-carbonitrile in analogy to the synthesis ofstep A of Example 27. The product accrues as a solid.

Mp.: 120° C.

C₂₄H₂₀N₂O₂ (368.4)

¹H-NMR (DMSO-d₆): δ (ppm)=3.95 (m, 2H), 4.19 (m, 1H), 4.32 (dd, J=14 Hzand J=7 Hz, 1H), 4.48 (dd, J=14 Hz and J=4 Hz, 1H), 5.49 (d, J=5 Hz,1H), 6.61 (d, J=3 Hz, 1H), 6.94 (m, 1H), 7.18 (d, J=2 Hz, 1H), 7.24 (d,J=8 Hz, 1H), 7.37 (m, 2H), 7.42-7.51 (m, 3H), 7.58 (d, J=3 Hz, 1H), 7.65(m, 2H), 7.72 (d, J=8 Hz, 1H), 8.09 (s, 1H)

B. 1-[3-(Biphenyl-3-yloxy)-2-hydroxypropyl]indole-5-carbamide

The preparation is based on1-[3-(biphenyl-3-yloxy)-2-hydroxypropyl]indole-5-carbonitrile in analogyto the synthesis of step C of Example 26. The product is obtained as asolid.

Mp.: 162° C.

C₂₄H₂₂N₂O₃ (386.4)

¹H-NMR (DMSO-d₆): δ (ppm)=3.95 (m, 2H), 4.20 (s, broad, 1H), 4.29 (dd,J=15 Hz and J=7 Hz, 1H), 4.42 (dd, J=15 Hz and J=4 Hz, 1H), 5.43 (s,broad, 1H), 6.45 (d, J=3 Hz, 1H), 6.97 (dd, J=8 Hz and J=2 Hz, 2H), 7.17(s, broad, 1H), 7.18 (d, J=2 Hz, 1H), 7.22 (d, J=8 Hz, 1H), 7.31-7.39(m, 2H), 7.41-7.51 (m, 3H), 7.60-7.69 (m, 3H), 7.84 (s, broad, 1H), 8.12(s, 1H)

C. 1-[3-(Biphenyl-3-yloxy)-2-oxopropyl]indole-5-carbamide

The preparation is based on1-[3-(biphenyl-3-yloxy)-2-hydroxypropyl]indole-5-carbamide in analogy tothe synthesis of step D of Example 26. The chromatographic purificationis initially carried out on silica gel using the flow agent hexane/ethylacetate 3:7 and then on an RP-HPLC column (cromasil) using the flowagent acetonitrile/water/formic acid (70:30:0.02). The product accruesas a solid.

C₂₄H₂₀N₂O₃ (384.4)

¹H-NMR (DMSO-d₆): δ (ppm)=5.18 (s, 2H), 5.44 (s, 2H), 6.58 (d, J=3 Hz,1H), 6.98 (dd, J=8 Hz and J=3 Hz, 1H), 7.18 (s, broad, 1H), 7.20-7.25(m, 2H), 7.25-7.45 (m, 6H), 7.60-7.71 (m, 3H), 7.83 (s, broad, 1H), 8.18(s, 1H)

EXAMPLE 29 1-[3-(Biphenyl-2-yloxy)-2-oxopropyl]indole-5-carbamide A.1-[3-(Biphenyl-2-yloxy)-2-hydroxypropyl]indole-5-carbonitrile

The preparation is based on 2-phenyl phenol and1-oxiranylmethylindole-5-carbonitrile in analogy to the synthesis ofstep A of Example 27. The product accrues as a solid.

Mp.: 117° C.

C₂₄H₂₀N₂O₂ (368.4)

¹H-NMR (DMSO-d₆): δ (ppm)=3.84 (dd, J=10 Hz and J=6 Hz, 1H), 3.94 (dd,J=10 Hz and J=4 Hz, 1H), 4.01-4.08 (m, 1H), 4.09-4.13 (m, 1H), 4.29-4.33(m, 1H), 5.41 (d, J=5 Hz, 1H), 6.57 (d, J=3 Hz, 1H), 7.01-7.11 (m, 2H),7.21-7.39 (m, 6H), 7.43-7.51 (m, 2H), 7.61 (d, J=7 Hz, 1H), 8.03 (s, 1H)

B. 1-[3-(Biphenyl-2-yloxy)-2-hydroxypropyl]indole-5-carbamide

The preparation is based on1-[3-(biphenyl-2-yloxy)-2-hydroxypropyl]indole-5-carbonitrile in analogyto the synthesis of step C of Example 26. The product is obtained as asolid.

Mp.: 150° C.

C₂₄H₂₂N₂O₃ (386.4)

¹H-NMR (DMSO-d₆): δ (ppm)=3.85 (dd, J=9 Hz and J=6 Hz, 1H), 3.92 (dd,J=9 Hz and J=4 Hz, 1H), 4.00-4.10 (m, 2H), 4.20-4.30 (m, 1H), 5.38 (d,J=4 Hz, 1H), 6.45 (d, J=3 Hz, 1H), 6.98-7.12 (m, 4H), 7.23 (d, J=3 Hz,1H), 7.25-7.50 (m, 5H), 7.52-7.61 (m, 3H), 7.81 (s, broad, 1H), 8.11 (s,1H)

C. 1-[3-(Biphenyl-2-yloxy)-2-oxopropyl]indole-5-carbamide

The preparation is based on1-[3-(biphenyl-2-yloxy)-2-hydroxypropyl]indole-5-carbamide in analogy tothe synthesis of step D of Example 26. The product accrues as a solid.

C₂₄H₂₀N₂O₃ (384.4)

¹H-NMR (DMSO-d₆): δ (ppm)=5.04 (s, 2H), 5.32 (s, 2H), 6.52 (d, J=3 Hz,1H), 7.01-7.83 (m, 13H), 7.91 (s, broad, 1H), 8.18 (d, J=1 Hz, 1H)

EXAMPLE 30 1-[3-(1-Heptylindol-5-yloxy)-2-oxopropyl]indole-5-carbamideA. 5-Benzyloxy-1-heptylindole

0.22 g (4.45 mmol) pulverized, 88% potassium hydroxide, 0.5 g (2.24mmol) 5-benzyloxyindole and 0.07 g (0.22 mmol) tetrabutylammoniumbromideare weighed out in the given order and mixed with 1.41 ml (8.96 mmol)1-bromoheptane with vigorous stirring. The mixture is stirred at roomtemperature overnight. Having added 30 ml water, three extractions usingdiethyl ether are carried out. The organic phase is washed three timeswith saturated NaCl solution, dried on sodium sulfate and the solvent isremoved in vacuo. The residue is purified on silica gel by means ofcolumn chromatography (flow agent: hexane/ethyl acetate 95:5). Theproduct accrues as an oil.

Yield: 530 mg (0.16 mmol), 74%

¹H-NMR (CDCl₃): δ (ppm)=0.80 (t, J=7 Hz, 3H), 1.13-1.27 (m, 8H), 1.75(quin, J=7 Hz, 2H), 4.00 (t, J=7 Hz, 2H), 5.05 (m, 2H), 6.31 (d, J=3 Hz,1H), 6.87 (dd, J=9 Hz and J=3 Hz, 1H), 6.98 (d, J=3 Hz, 1H), 7.08 (d,J=3 Hz, 1H), 7.16 (d, J=9 Hz, 1H), 7.24 (t, J=7 Hz, 1H), 7.31 (m, 2H),7.41 (d, J=7 Hz, 2H)

B. 1-Heptylindol-5-ol

0.5 g (1.55 mmol) 5-benzyloxy-1-heptylindole is dissolved in a Schlenkflask in 10 ml methanol and 4 ml dichloromethane. 0.06 g Pd (10%)/C isadded and the mixture is rinsed with nitrogen for 15 minutes.Thereafter, a balloon filled with hydrogen is placed on the Schlenkpiston and hydrogenation is carried out at room temperature for 12 h.The batch is filtrated on a frit and the solvent is removed in vacuo.The residue is purified on silica gel by means of column chromatography(flow agent: hexane/ethyl acetate 9:1). The product accrues as an oil.

Yield: 0.33 g (1.43 mmol); 90%

C₂₄H₂₀N₂O₃ (384.4)

¹H-NMR (DMSO-d₆): δ (ppm)=0.82 (t, J=7 Hz, 3H), 1.21 (m, 8H), 1.72(quin, J=7 Hz, 2H), 4.05 (t, J=7 Hz, 2H), 6.18 (d, J=3 Hz, 1H), 6.61(dd, J=9 Hz and J=2 Hz, 1H), 6.82 (d, J=2 Hz, 1H), 7.20 (m, 2H), 8.63(s, 1H).

C. 1-[3-(1-Heptylindol-5-yloxy)-2-hydroxypropyl]indole-5-carbonitrile

The preparation is based on 1-heptylindol-5-ol and1-oxiranylmethylindole-5-carbonitrile in analogy to the synthesis ofstep B of Example 26. The chromatographic purification on silica gel iscarried out using the flow agent hexane/ethyl acetate 4:1. The productaccrues as an oil.

C₂₇H₃₁N₃O₂ (429.6)

¹H-NMR (DMSO-d₆): δ (ppm)=0.83 (t, J=7 Hz, 3H), 1.13-1.28 (m, 8H), 1.71(quin, J=7 Hz, 2H), 3.81-3.91 (m, 1H), 4.02 (m, 1H), 4.08 (t, J=7 Hz,2H), 4.15 (s, broad, 1H), 4.31 (dd, J=14 Hz and J=7 Hz, 1H), 4.46 (dd,J=14 Hz and J=4 Hz, 1H), 5.41 (s, broad, 1H), 6.28 (d, J=3 Hz, 1H), 6.58(d, J=3 Hz, 1H), 6.80 (dd, J=9 Hz and J=2 Hz, 1H), 6.95 (d, J=2 Hz, 1H),7.28 (d, J=3 Hz, 1H), 7.34 (d, J=9 Hz, 1H), 7.42 (dd, J=9 Hz and J=2 Hz,1H), 7.44 (d, J=3 Hz, 1H), 7.68 (d, J=9 Hz, 1H), 8.06 (d, J=2 Hz, 1H)

D. 1-[3-(1-Heptylindol-5-yloxy)-2-hydroxypropyl]indole-5-carbamide

The preparation is based on1-[3-(1-heptylindol-5-yloxy)-2-hydroxypropyl]indole-5-carbonitrile inanalogy to the synthesis of step C of Example 26. The product accrues asa solid.

Mp.: 114° C.

C₂₇H₃₃N₃O₃ (447.6)

¹H-NMR (DMSO-d₆): δ (ppm)=0.83 (t, J=7 Hz, 3H), 1.13-1.28 (m, 8H), 1.71(quin, J=7 Hz, 2H), 3.81-3.91 (m, 1H), 4.02 (q, J=7 Hz, 1H), 4.08 (t,J=7 Hz, 2H), 4.15 (m, 1H), 4.31 (dd, J=14 Hz and J=7 Hz, 1H), 4.46 (dd,J=14 Hz and J=4 Hz, 1H), 5.40 (d, J=5 Hz, 1H), 6.28 (d, J=3 Hz, 1H),6.48 (d, J=3 Hz, 1H), 6.80 (dd, J=9 Hz and J=2 Hz, 1H), 6.95 (d, J=2 Hz,1H), 7.08 (s, broad, 1H), 7.28 (d, J=3 Hz, 1H), 7.34 (d, J=9 Hz, 1H),7.42 (dd, J=9 Hz and J=2 Hz, 1H), 7.44 (d, J=3 Hz, 1H), 7.68 (d, J=9 Hz,1H), 7.81 (s, broad, 1H), 8.12 (d, J=2 Hz, 1H)

E. 1-[3-(1-Heptylindol-5-yloxy)-2-oxopropyl]indole-5-carbamide

The preparation is based on1-[3-(1-heptylindol-5-yloxy)-2-hydroxypropyl]indole-5-carbamide inanalogy to the synthesis of step C of Example 9. Deviating therefrom,the reaction time is 20 h. The product is extracted from the reactionbatch by means of ethyl acetate. The chromatographic purification onsilica gel is made using the flow agent ethyl acetate. Followingrecrystallization from hexane/ethyl acetate, the product accrues as asolid.

Mp.: 171° C.

C₂₇H₃₁N₃O₃ (445.6)

¹H-NMR (DMSO-d₆): δ (ppm)=0.83 (t, J=7 Hz, 3H), 1.13-1.28 (m, 8H), 1.71(quin, J=7 Hz, 2H), 4.08 (t, J=7 Hz, 2H), 4.97 (s, 2H), 5.42 (s, 2H),6.28 (d, J=3 Hz, 1H), 6.48 (d, J=3 Hz, 1H), 6.80 (dd, J=9 Hz and J=2 Hz,1H), 6.95 (d, J=2 Hz, 1H), 7.12 (s, broad, 1H), 7.28 (d, J=3 Hz, 1H),7.34 (d, J=9 Hz, 1H), 7.42 (dd, J=9 Hz and J=0 2 Hz, 1H), 7.44 (d, J=3Hz, 1H), 7.68 (d, J=9 Hz, 1H), 7.82 (s, broad, 1H), 8.12 (d, J=2 Hz, 1H)

EXAMPLE 31 Pharmacological Test

The effectiveness of the compounds according to the invention can bedetermined by the inhibition of cytosolic phospholipase A₂. The testmethod used was described earlier (Lehr M. et al., Arch. Pharm. Pharm.Med. Chem. 2000, 333, 312-314). Here, the arachidonic acid formed bycytosolic phospholipase A₂ in intact human platelets followingstimulation using calcium ionophor A23187 is detected in the presenceand absence of test substances.

The compounds of Examples 2, 5, 6, 7, 8 and 9 according to the inventionwere tested by means of this test system. At a concentration of 10 μMthey inhibited the activity of cytosolic phospholipase A₂ by 40% to 95%,which proves their effectiveness.

1. A compound of formula I

wherein Q represents R¹, OR¹, SR¹, SOR¹, SO₂R¹, NR⁹R¹ or a straight-chain C₁₋₃₁ alkyl or C₂₋₃₁ alkenyl or alkinyl group which is optionally interrupted by 1 or 2 groups, independently selected from O, S, SO, SO₂, NR⁹ and aryl which are optionally substituted with 1 or 2 substituents R⁴, and which are optionally substituted with 1-4 C₁₋₆ alkyl groups and/or 1 or 2 aryl groups, wherein the aryl groups is optionally substituted with 1 or 2 substituents R⁴; Ar represents an aryl group selected from the group consisting of a phenyl, naphthyl, biphenyl, and 5-membered heterocylic ring and 6-membered heterocyclic ring, said aryl group containing 1 to 3 atoms selected from O, N, or S and optionally annellated using a benzene ring and further which is optionally substituted with 1 or 2 substituents R⁴; X represents N or CR⁵; Y represents N or CR⁶; R¹ represents H or an aryl group which is optionally substituted with 1 or 2 substituents R⁴; R² and R³ a) independently stand for H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl or R⁷—W, or b) together with the carbon atoms to which they are bound, form a 5- or 6-membered aromatic or heteroaromatic ring which is optionally substituted with 1 or 2 substituents R⁴; R⁴ represents C₁₋₆ alkyl, halogen, CF₃, CN, NO₂, OR⁹, S(O)₀R⁹, COR⁹, COOR⁹, CONR⁹R¹⁰, SO₃R⁹, SO₂NR⁹R¹⁰, tetrazolyl or R⁷—W R⁵ represents H or R⁴; R⁶ represents H, C₁₋₆ alkyl, halogen, CF₃, CN, NO₂, OR⁹, S(O)₀R⁹, COR⁹, COOR⁹, CONR⁹R¹⁰, SO₃R⁹, SO₂NR⁹R¹⁰, tetrazolyl or R⁸—W; R⁷ represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl; R⁸ represents C₂₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl; R⁹ represents H, C₁₋₆ alkyl or aryl; R¹⁰ represents H or C₁₋₆ alkyl; W represents COOH, SO₃H or tetrazolyl; and o represents 0, 1 or 2; and the pharmaceutically compatible salts and esters thereof.
 2. The compound according to claim 1, wherein Q represents R¹—(CHR¹¹)_(p)—A—Z²—B—Z¹— wherein A represents a bond or a straight-chain C_(1-m) alkyl residue or C_(2-m) alkenyl or alkinyl group; B represents a bond or a straight chain C_(1-n) alkyl residue or C_(2-n) alkenyl or alkynyl group; R¹¹ represents H or an aryl group which is optionally substituted with 1 or 2 substituents R⁴; Z¹ and Z² independently represent a bond, O, S, SO, SO₂, NR⁹, CR⁹R¹⁰ or an aryl group, wherein the aryl group is optionally substituted with 1 or 2 substituents R⁴; R¹, R⁴, R⁹ and R¹⁰ are as defined in claim 1; p represents 0 or 1; m represents an integer from 0 to 12; and n represents an integer from 0 to
 16. 3. The compound according to claim 2, wherein m+n≦17.
 4. The compound according to claim 2, wherein Q is selected from the group consisting of: R¹—B—Z¹— R¹—CHR¹¹—B—Z¹— R¹—A—Z²—B—Z¹— and R¹—CHR¹¹—A—Z²—B—Z¹—, Wherein A, B, R¹, R¹¹, Z¹, Z², n and m are as defined in claim
 2. 5. The compound according to claim 4, wherein Q represents phenyl or C₅₋₁₂ alkyl or alkoxy.
 6. The compound according to claim 1, wherein Ar represents a phenyl or indolyl group.
 7. The compound according to claim 1, wherein R² and R³ a) independently represent H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl or R⁷—W or b) together with the carbon atoms to which they are bound form a benzo ring or a 6-membered aromatic heterocyclic ring having 1-3 nitrogen atoms, wherein the benzo ring or the heterocyclic ring is optionally substituted with 1 or 2 substituents R⁴, and R⁴ is defined as in claim
 1. 8. The compound according to claim 7, wherein R² and R³ represent H or together with the carbon atoms to which they are bound form a benzo ring which is optionally substituted with a substituent R⁴.
 9. The compound according to claim 1, wherein X═CR⁵ and Y═CR⁶ or X═N and Y═CR⁶, wherein R⁵ and R⁶ are as defined in claim
 1. 10. A pharmaceutical preparation comprising a compound of general formula I according to claim 1 or a pharmaceutically compatible salt or ester thereof.
 11. A method of producing a compound of formula I according to claim 1, wherein a compound of formula II

or a compound of formula III

is reacted with a compound of formula IV

and the alcohol formed is oxidized into the desired ketone, wherein Q, Ar, X, Y, R² and R³ are as defined in claim 1 and Abg represents a leaving group.
 12. The compound according to claim 3, wherein Q is selected from R¹—B—Z¹— R¹—CHR¹¹—B—Z¹— R¹—A—Z²—B—Z¹— and R¹—CHR¹¹—A—Z²—B—Z¹—.
 13. The compound according to claim 4, wherein Q represents phenyl or C₅₋₁₂ alkyl or alkoxy.
 14. The compound according to claim 5, wherein Q represents C₇₋₁₀ alkyl or alkoxy.
 15. The compound according to claim 8, wherein substituent R⁴ is selected from the group consisting of COOH, CH₃, Cl, OCH₃, CN, CHO, COOCH₃ and CONH₂.
 16. The compound according to claim 9, wherein R⁵ and R⁶ are independently selected from the group consisting of H, COOH, t-butyl, Cl, CHO, COCH₃ and COOCH₃.
 17. The compound according to claim 13, wherein Q represents C₇₋₁₀ alkyl or alkoxy.
 18. The method according to claim 11, wherein the leaving group is a halogen. 